Substituted piperidine compounds and methods of their use

ABSTRACT

Novel 3,4-disubstituted-4-aryl-piperidine compounds are disclosed. Pharmaceutical compositions containing the 3,4-disubstituted-4-aryl-piperidine compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as antagonists of opioid receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/462,507, filed Jun. 16, 2003, now U.S. Pat. No. 6,992,090, issuedJan. 31, 2006, which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to compounds that affect the opioidreceptor system and, more particularly, to3,4-disubstituted-4-aryl-piperidine compounds and pharmaceuticalcompositions containing such compounds that are, inter alia, antagonistsof opioid receptors.

BACKGROUND OF THE INVENTION

It is well known that opioid drugs target three types of endogenousopioid receptors (i.e., μ, δ, and κ receptors) in biological systems.Many opiates, such as morphine, are μ opioid agonists that are oftenused as analgesics for the treatment of severe pain due to theiractivation of μ opioid receptors in the brain and central nervous system(CNS). Opioid receptors are, however, not limited to the CNS, and may befound in other tissues throughout the body, i.e., peripheral to the CNS.A number of side effects of opioid drugs may be caused by activation ofthese peripheral receptors. For example, administration of μ opioidagonists often results in intestinal dysfunction due to the large numberof receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle, D.,Biochemical and Biophysical Research Communications, 1996, 218, 877-881;Bagnol, D., Mansour, A., Akil, A. and Watson, S. J., Neuroscience, 1997,81, 579-591). Specifically, opioids are generally known to cause nauseaand vomiting, as well as inhibition of normal propulsivegastrointestinal function in animals and man (Reisine, T., andPasternak, G., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Ninth Edition, 1996, 521-555), resulting in side effectssuch as, for example, constipation.

Recent evidence has indicated that naturally-occurring endogenous opioidcompounds may also affect propulsive activity in the gastrointestinal(GI) tract. Met-enkephalin, which activates μ and δ receptors in boththe brain and gut, is one of several neuropeptides found in the GI tract(Koch, T. R., Carney, J. A., Go, V. L., and Szurszewski, J. H.,Digestive Diseases and Sciences, 1991, 36, 712-728). Additionally,receptor knockout techniques have shown that mice lacking μ opioidreceptors may have faster GI transit times than wild-type mice,suggesting that endogenous opioid peptides may tonically inhibit GItransit in normal mice (Schuller, A. G. P., King, M., Sherwood, A. C.,Pintar, J. E., and Pasternak, G. W., Society of Neuroscience Abstracts1998, 24, 524). Studies have shown that opioid peptides and receptorslocated throughout the GI tract may be involved in normal regulation ofintestinal motility and mucosal transport of fluids in both animals andman (Reisine, T., and Pasternak, G., Goodman & Gilman's ThePharmacological Basis of Therapeutics, Ninth Edition, 1996, 521-555).Other studies show that the sympathetic nervous system may be associatedwith endogenous opioids and control of intestinal motility (Bagnol, D.,Herbrecht, F., Jule, Y., Jarry, T., and Cupo, A., Regul. Pept., 1993,47, 259-273). The presence of endogenous opioid compounds associatedwith the GI tract suggests that an abnormal physiological level of thesecompounds may lead to bowel dysfunction.

It is a common problem for patients having undergone surgicalprocedures, especially surgery of the abdomen, to suffer from aparticular bowel dysfunction called post-surgical (or post-operative)ileus. “Ileus,” as used herein, refers to the obstruction of the bowelor gut, especially the colon. See, e.g., Dorland's Illustrated MedicalDictionary, 27th ed., page 816, (W.B. Saunders Company, Philadelphia,Pa., 1988). Ileus should be distinguished from constipation, whichrefers to infrequency of or difficulty in feces evacuation. See, e.g.,Dorland's Illustrated Medical Dictionary, 27th ed., page 375, (W. B.Saunders Company, Philadelphia,1988). Ileus may be diagnosed by thedisruption of normal coordinated movements of the gut, resulting infailure of intestinal contents propulsion. See, e.g., Resnick, J., Am.J. of Gastroenterology, 1997, 92, 751 and Resnick, J. Am. J. ofGastroenterology, 1997, 92, 934. In some instances, particularlyfollowing surgery, including surgery of the abdomen, the boweldysfunction may become quite severe, lasting for more than a week andaffecting more than one portion of the GI tract. This condition is oftenreferred to as post-surgical (or post-operative) paralytic ileus andmost frequently occurs after laparotomy (see Livingston, E. H. andPassaro, Jr., E. D., Digestive Diseases and Sciences, 1990, 35, 121).Similarly, post-partum ileus is a common problem for women in the periodfollowing childbirth, and is thought to be caused by similarfluctuations in natural opioid levels as a result of birthing stress.

Gastrointestinal dysmotility associated with post-surgical ileus isgenerally most severe in the colon and typically lasts for 3 to 5 days.The administration of opioid analgesics to a patient after surgery mayoften contribute to bowel dysfunction, thereby delaying recovery ofnormal bowel function. Since virtually all patients receive opioidanalgesics, such as morphine or other narcotics, for pain relief aftersurgery, particularly major surgery, current post-surgical paintreatment may actually slow recovery of normal bowel function, resultingin a delay in hospital discharge and increasing the cost of medicalcare.

Post-surgical and post-partum ileus may also occur in the absence ofexogenous opioid agonists. It would be of benefit to inhibit the naturalactivity of endogenous opioids during and/or after periods of biologicalstress, such as surgery and childbirth, so that ileus and related formsof bowel dysfunction can be prevented and/or treated. Currently,therapies for ileus include functional stimulation of the intestinaltract, stool softeners, laxatives, lubricants, intravenous hydration,and nasogastric decompression. These prior art methods suffer fromdrawbacks, for example, as lacking specificity for post-surgical orpost-partum ileus. And these prior art methods offer no means forprevention. If ileus could be prevented, hospital stays, recovery times,and medical costs would be significantly decreased, in addition to thebenefit of minimizing patient discomfort. Thus, drugs that selectivelyact on opioid receptors in the gut would be ideal candidates forpreventing and/or treating post-surgical and post-partum ileus. Ofthose, drugs that do not interfere with the effects of opioid analgesicsin the CNS would be of special benefit in that they could beadministered simultaneously for pain management with limited sideeffects.

Peripheral opioid antagonists that do not cross the blood-brain barrierinto the CNS are known in the literature and have been tested inrelation to their activity on the GI tract. In U.S. Pat. No. 5,250,542,U.S. Pat. No. 5,434,171, U.S. Pat. No. 5,159,081, and U.S. Pat. No.5,270,328, peripherally selective piperidine-N-alkylcarboxylate opioidantagonists are described as being useful in the treatment of idiopathicconstipation, irritable bowel syndrome, and opioid-induced constipation.In addition, U.S. Pat. No. 4,176,186 describes quaternary derivatives ofnoroxymorphone (i.e., methylnaltrexone) that are said to prevent orrelieve the intestinal immobility side effect of narcotic analgesicswithout reducing analgesic effectiveness. U.S. Pat. No. 5,972,954describes the use of methylnaltrexone, enteric-coated methylnaltrexone,or other quaternary derivatives of noroxymorphone for preventing and/ortreating opioid- and/or nonopioid-induced side effects associated withopioid administration.

General opioid antagonists, such as naloxone and naltrexone, have alsobeen implicated as being useful in the treatment of GI tractdysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek, M. J.Schaefer, R. A., Hahn, E. F., Fishman, J. Lancet, 1983, 1, 8319, 261disclose naloxone and other morphinan-based opioid antagonists (i.e.,naloxone, naltrexone) for the treatment of idiopathic gastrointestinaldysmotility. In addition, naloxone has been shown to effectively treatnon-opioid induced bowel obstruction, implying that the drug may actdirectly on the GI tract or in the brain (Schang, J. C., Devroede, G.,Am. J. Gastroenerol., 1985, 80, 6, 407). Furthermore, it has beenimplicated that naloxone may provide therapy for paralytic ileus (Mack,D. J. Fulton, J. D., Br. J. Surg., 1989, 76, 10, 1101). However, it iswell known that activity of naloxone and 7related drugs is not limitedto peripheral systems and may interfere with the analgesic effects ofopioid narcotics.

Inasmuch as post-surgical and post-partum ileus, for example, are commonillnesses that add to the cost of health care and as yet have nospecific treatments, there is a need for a specific and effectiveremedy. The majority of currently known opioid antagonist therapies isnot peripherally selective and has the potential for undesirable sideeffects resulting from penetration into the CNS. Given the estimated 21million inpatient surgeries and 26 million outpatient surgeries eachyear, and an estimate of 4.7 million patients experiencing post-surgicalileus, methods involving opioid antagonists that are not only specificfor peripheral systems, but also specific for the gut, are desirable fortreating post-surgical and post-partum ileus.

There is still an unfulfilled need for compounds that may be used inmethods to antagonize opioid receptors, particularly where undesirablesymptoms or conditions are side effects of administering exogenousopioids. The present invention is directed to these, as well as otherimportant ends.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed, in part, to novelpharmaceutically active compounds of formula I:

-   -   wherein:        -   R¹ is H or alkyl;        -   R^(2a) is alkyl or alkenyl;        -   R^(2b) is H, alkyl, or alkenyl;        -   R³ is H, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,            cycloalkylalkyl, cycloalkenylalkyl, or aralkyl;        -   R⁴ is:            -   H,            -   aryl (optionally substituted by one or more substituents                selected from —OH, nitro, halo, —CN, —CH₂CN, —C(═O)NH₂,                —CO₂H, —N(R^(6a))(R^(6b)), alkoxycarbonyl, aryloxy,                aryl, alkyl, alkoxy, and alkanoyl (which latter three                groups are optionally substituted by one or more halo                atoms)),            -   aralkyl,            -   alkyl,            -   alkenyl, or            -   alkynyl,            -   which latter three groups are optionally substituted by                one or more substituents selected from —OR^(6c),                —S(═O)_(q)R^(6d), —CN, halo, alkoxycarbonyl,                —N(R^(6a))(R^(6b)), alkanoyl, alkanoyloxy, cycloalkyl,                cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a),                —P(═O)OR^(7b)OR^(7c), Het¹, and aryl (which latter group                is optionally substituted by one or more substituents                selected from —OH, nitro, —N(R^(6a))(R^(6b)), halo, —CN,        -   —CH₂CN, —C(═O)NH₂, —CO₂H, —CHO, aryl, alkyl, alkoxy,            aralkoxy, aryloxy, and alkanoyl (which latter three groups            are optionally substituted by one or more halo atoms));        -   R^(6a), R^(6b), R^(6c), R^(6d), and R^(6e), are each            independently H, Het², alkyl, alkenyl, alkynyl, cycloalkyl,            aralkyl, or aryl (which latter six groups are optionally            substituted by one or more substituents selected from OH,            nitro, halo, —NHC(═O)R³, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,            alkoxycarbonyl, alkyl, alkoxy, and alkanoyl (which latter            three groups are optionally substituted by one or more halo            atoms));        -   R⁵ is —(CH₂)_(y)(CHR⁸)_(j)(CHR^(8a))_(z)W,            —CH₂P(═O)OR^(7b)OR^(7c), or —S(═O)₂R^(7d);        -   R⁸ is each independently aryl (optionally substituted by one            or more substituents selected from —OH, nitro, aryl, halo,            —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, —N(R^(6a))(R^(6b)), alkyl,            alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)),            cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl,            alkenyl or alkynyl groups are optionally substituted by one            or more substituents selected from —OR^(6c),            —S(O)_(q)R^(6d), —CN, halo, —N(R^(6a))(R^(6b)), —CO₂H,            —C(═O)NH₂, alkoxycarbonyl, alkanoyl, alkanoyloxy,            cycloalkyl, cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a),            —P(═O)OR^(7b)OR^(7c), Het¹, and aryl (which latter group is            optionally substituted by one or more substituents selected            from —OH, nitro, amino, halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,            aroyl, aryl, alkyl, alkoxy, and alkanoyl (which latter three            groups are optionally substituted by one or more halo            atoms)); or R⁴ and R⁸ when taken together with the atoms            through which they are connected, form a 4- to 8-membered            heterocycloalkyl ring, wherein said heterocycloalkyl ring is            optionally fused to an aromatic ring, and wherein said            heterocycloalkyl ring, or the aromatic ring to which it is            optionally fused, is each independently optionally            substituted by one or more substituents selected from —OH,            alkyl, or alkoxy; and wherein the heterocycloalkyl ring is            also optionally interrupted by one or more O, S or N(R¹¹)            groups;        -   R^(8a) is each independently H, aryl (optionally substituted            by one or more substituents selected from —OH, nitro, aryl,            halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, —N(R^(6a))(R^(6b)),            alkyl, alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)),            cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl,            alkenyl or alkynyl groups are optionally substituted by one            or more substituents selected from —OR^(6c),            —S(O)_(q)R^(6d), —CN, halo, amino, —CO₂H, —C(═O)NH₂,            alkoxycarbonyl, alkanoyl, alkanoyloxy, cycloalkyl,            cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c),            Het¹, and aryl (which latter group is optionally substituted            by one or more substituents selected from —OH, nitro, amino,            halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, aroyl, aryl, alkyl,            alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)); or R⁴            and R^(8a) when taken together with the atoms through which            they are connected, form a 4- to 8-membered heterocycloalkyl            ring, wherein said heterocycloalkyl ring is optionally fused            to an aromatic ring, and wherein said heterocycloalkyl ring,            or the aromatic ring to which is optionally fused, is each            independently optionally substituted by one or more            substituents selected from —OH, alkyl, or alkoxy; and            wherein the heterocycloalkyl ring is also optionally            interrupted by one or more O, S or N(R¹¹) groups;        -   W is —C(═O)OR⁹, —C(═O)N(R^(10a))(R^(10b)), or            —P(═O)OR^(7b)OR^(7c);        -   R⁹ is H, alkyl, alkenyl, phenyl, cycloalkyl, cycloalkenyl,            cycloalkylalkyl, cycloalkenylalkyl, or aralkyl;        -   R^(10a) and R^(10b), each independently represent H, alkyl,            alkenyl, alkynyl, cycloalkyl, aralkyl, Het³, or aryl (which            latter seven groups are optionally substituted by one or            more substituents selected from —OH, nitro, halo, —CN,            —CH₂CN, —C(═O)NH₂, —CO₂H, alkyl, alkoxy, and alkanoyl (which            latter three groups are optionally substituted by one or            more halo atoms)); or R^(10a) and R^(10b) when taken            together with the nitrogen atom to which they are attached            form a 4- to 8-membered heterocycloalkyl ring, wherein said            heterocycloalkyl ring is optionally fused to an aromatic            ring, and wherein said heterocycloalkyl ring, or the            aromatic ring to which it is optionally fused, is each            independently optionally substituted by one or more            substituents selected from —OH, alkyl, or alkoxy; and            wherein the heterocycloalkyl ring is also optionally            interrupted by one or more O, S or N(R¹²) groups;        -   R^(7a), R^(7b), R^(7c), and R^(7d), are each independently            H, alkyl, cycloalkyl, alkaryl, aralkyl or aryl, which latter            five groups are optionally substituted by one or more            substituents selected from alkyl, alkoxy, —OH, nitro, amino            and halo;        -   Het¹, Het² and Het³ each independently represent a 3- to            8-membered heterocyclic ring, wherein said heterocyclic ring            contains at least one heteroatom selected from oxygen,            sulfur, nitrogen or combinations thereof, wherein said            heterocyclic ring is optionally fused to an aromatic ring,            and wherein said heterocyclic ring, or the aromatic ring to            which it is optionally fused, is each independently            optionally substituted by one or more substituents selected            from —OH, ═O, nitro, amino, halo, —CN, —CO₂H, aryl, alkyl,            alkoxy and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms);        -   R¹¹ represents H, alkyl, cycloalkyl, cycloalkylalkyl, or            aralkyl;        -   R¹² represents H, alkyl, cycloalkyl, cycloalkylalkyl, or            aralkyl;        -   j is the integer 0, 1, 2, 3, or 4;        -   m is the integer 0, 1, 2, 3, or 4;        -   q is the integer 0, 1, or 2;        -   y is the integer 0, 1, 2, 3, 4, or 5; and        -   z is the integer 0, 1, 2, 3, or 4;        -   with the provisos that:            -   when j and z are each the integer 0, y must be the                integer 5; and            -   when R^(8a) is H and j is 0, the sum of y+z must be the                integer 5;    -   or a stereoisomer, prodrug, pharmaceutically acceptable salt,        hydrate, solvate, acid hydrate, N-oxide or isomorphic        crystalline form thereof.

In another embodiment, the invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I.

In yet another embodiment, the invention is directed to methods forbinding opioid receptors, in a patient in need thereof, comprising thestep of:

administering to said patient an effective amount of a compound offormula I.

In other embodiments, the invention is directed to methods for bindingopioid receptors, comprising the step of:

administering to said patient an effective amount of a compound offormula I;

where the 3,4-disubstituted-4-aryl-piperidine compound exhibits activitytoward the opioid receptors (selected from μ, κ, or combinationsthereof).

In some preferred embodiments, the invention is directed to methodswhere the patient is in need of prevention or treatment of a condition,disease or undesirable side effect caused by an endogenous or exogenousopioid.

In a particularly preferred embodiment, the invention is directed tomethods for preventing or treating gastrointestinal dysfunction.

In yet another preferred embodiment, the invention is directed tomethods of preventing or treating pain, comprising the step of:

administering to a patient in need thereof, a composition, comprising aneffective amount of an opioid; and an effective amount of a compound offormula I.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, “alkyl” refers to an optionally substituted, saturatedstraight, or branched, hydrocarbon having from about 1 to about 10carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein). In some embodiments, it ispreferred that the alkyl groups have from about 1 to about 4 carbonatoms. In others, it is preferred that the alkyl groups have from about1 to about 5 carbon atoms. In still others, it is preferred that thealkyl groups have from about 1 to about 6 carbon atoms. Alkyl groups canbe optionally substituted. Alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl.

As used herein, “alkenyl” refers to an alkyl group having from about 2to about 10 carbon atoms and one or more double bonds (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), wherein alkyl is as previously defined. In someembodiments, it is preferred that the alkenyl groups have from about 2to about 6 carbon atoms. Alkenyl groups can be optionally substituted.

As used herein, “alkynyl” refers to an alkyl group having from about 2to about 10 carbon atoms and one or more triple bonds (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), wherein alkyl is as previously defined. Alkynylgroups can be optionally substituted.

As used herein, “aryl” and “aromatic” each refer to an optionallysubstituted, mono-, di-, tri-, or other multicyclic aromatic ring systemhaving from about 5 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 6 to about 10 carbons being preferred. Exemplary arylgroups include, but are not limited to, phenyl, naphthyl, anthracenyl,and phenanthrenyl.

As used herein, “aralkyl” refers to alkyl radicals bearing one or morearyl substituents and having from about 6 to about 50 carbon atoms (andall combinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), wherein aryl and alkyl are as previously defined.In some preferred embodiments, the alkyl moieties of the aralkyl groupshave from about 1 to about 4 carbon atoms. In other preferredembodiments, the alkyl moieties have from about 1 to about 3 carbonatoms. Aralkyl groups can be optionally substituted. Exemplary aralkylgroups include, but are not limited to, benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl.

As used herein, “alkaryl” refers to an optionally substituted, mono-,di-, tri-, or other multicyclic aryl radical bearing one or more alkylsubstituents and having from about 5 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), and wherein aryl and alkyl are as previouslydefined. In some preferred embodiments, the alkyl substituents of thealkaryl groups have from about 1 to about 4 carbon atoms. Alkaryl groupscan be optionally substituted. Exemplary alkaryl groups include, but arenot limited to, tolyl, xylyl, 1-methylnaphthyl, 9-ethylanthracenyl, and2,4-dimethylphenanthrenyl.

As used herein, “heteroaryl” refers to an optionally substituted, mono-,di-, tri-, or other multicyclic aromatic ring system that includes atleast one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogenheteroatom ring members. Heteroaryl groups can have, for example, fromabout 3 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 4 to about 10 carbons being preferred. Exemplaryheteroaryl groups include, but are not limited to, pyrryl, furyl,pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,carbazolyl, benzimidazolyl, and isoxazolyl.

As used herein, “cycloalkyl” refers to an optionally substituted, alkylgroup having one or more rings in their structure and having from about3 to about 20 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein). In some preferredembodiments, the cycloalkyl groups have from about 3 to about 8 carbonatoms. Multi-ring structures may be bridged or fused ring structures,wherein the additional groups fused or bridged to the cycloalkyl ringmay include optionally substituted cycloalkyl, aryl, heterocycloalkyl,or heteroaryl rings. Exemplary cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclooctyl, adamantyl,2-[4-isopropyl-1-methyl-7-oxa-bicyclo[2.2.1]heptanyl], and2-[1,2,3,4-tetrahydro-naphthalenyl].

As used herein, “cycloalkenyl” refers to an optionally substituted,alkyl group having one or more rings in their structure, wherein thering is partially unsaturated, that is, having one or more double bondswithin the ring, and having from about 3 to about 20 carbon atoms (andall combinations and subcombinations of ranges and specific numbers ofcarbon atoms therein). In some preferred embodiments, the cycloalkenylgroups have from about 5 to about 8 carbon atoms. Multi-ring structuresmay be bridged or fused ring structures, wherein the additional groupsfused or bridged to the cycloalkenyl ring may include optionallysubstituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl rings.Exemplary cycloalkenyl groups include, but are not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl,bicyclo[2.2.1 ]hept-5-en-2-yl, bornenyl, [2.2.2]-bicyclooct-5-en-2-yl,octahydronaphthalenyl, beta-pinenyl, camphenyl, fenchenyl, α-pinenyl,and dicyclopentadienyl.

As used herein, “alkylcycloalkyl” refers to an optionally substitutedring system comprising a cycloalkyl radical having one or more alkylsubstituents, wherein cycloalkyl and alkyl are as previously defined.Exemplary alkylcycloalkyl groups include, but are not limited to,2-methylcyclohexyl, 3,3-dimethylcyclopentyl,trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.

As used herein, “cycloalkylalkyl” refers to an optionally substitutedalkyl radical having one or more cycloalkyl substituents, whereincycloalkyl and alkyl are as previously defined. In some preferredembodiments, the alkyl moieties of the cycloalkylalkyl groups have fromabout 1 to about 3 carbon atoms. Exemplary cycloalkylalkyl groupsinclude, but are not limited to, cyclohexylmethyl,4-[4-methyldecahydronaphthalenyl]-pentyl,3-[trans-2,3-dimethylcyclooctyl]-propyl, and cyclopentylethyl.

As used herein, “cycloalkenylalkyl” refers to an optionally substitutedalkyl radical having one or more cycloalkenyl substituents, whereincycloalkenyl and alkyl are as previously defined. In some preferredembodiments, the alkyl moieties of the cycloalkenylalkyl groups havefrom about 1 to about 3 carbon atoms. Exemplary cycloalkenylalkyl groupsinclude, but are not limited to,4-[4-methyloctahydronaphthalenyl]-pentyl, cyclohexenylmethyl,3-[trans-2,3-dimethylcyclooctenyl]-propyl, and cyclopentenylethyl.

As used herein, “heteroaralkyl” refers to optionally substituted alkylradicals having one or more heteroaryl substituents and theheteroaralkyl groups having from about 2 to about 50 carbon atoms (andall combinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), wherein heteroaryl and alkyl are as previouslydefined. In some preferred embodiments, the heteroaralkyl groups havefrom about 6 to about 25 carbon atoms. Non-limiting examples include,but are not limited to, 5-(2H-tetrazolyl)methyl,2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, and3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

As used herein, “heterocyclic” refers to an optionally substitutedheteroaryl or heterocycloalkyl ring, wherein heteroaryl andheterocycloalkyl are as previously defined. In some preferredembodiments, the heterocyclic groups have from about 3 to about 8 carbonatoms.

As used herein, “heterocycloalkyl” refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aliphatic ring system thatincludes at least one, and preferably from 1 to about 4 sulfur, oxygen,or nitrogen heteroatom ring members. Heterocycloalkyl groups can havefrom about 3 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein).In some preferred embodiments the heterocyclic groups have from about 4to about 8 carbons. In other embodiments the heterocycloalkyl group maybe unsaturated, that is to say, they have one or more double bonds. Instill other embodiments, the heterocyclic groups may be fused toaromatic rings. Exemplary heterocycloalkyl groups include, but are notlimited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl,decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta[c]pyranyl,1,2,3,4,-tetrahydroquinolyl, octahydro-[2]pyrindinyl,decahydro-cycloocta[c]furanyl, tetrahydroquinolyl, and imidazolidinyl.

As used herein, the term “spiroalkyl” refers to an optionallysubstituted, alkylene diradical, both ends of which are bonded to thesame carbon atom of the parent group to form a spirocyclic group. Thespiroalkyl group, taken together with its parent group, as hereindefined, has 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms.Exemplary spiroalkyl groups taken together with its parent groupinclude, but are not limited to, 1-(1-methyl-cyclopropyl)-propan-2-one,2-(1-phenoxy-cyclopropyl)-ethylamine, and 1-methyl-spiro[4.7]dodecane.

As used herein, the term “alkoxy” refers to an optionally substitutedalkyl-O— group wherein alkyl is as previously defined. In some preferredembodiments the alkyl moieties of the alkoxy groups have from about 1 toabout 4 carbon atoms. Exemplary alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, andheptoxy.

As used herein, the term “aryloxy” refers to an optionally substitutedaryl-O— group wherein aryl is as previously defined. Exemplary aryloxygroups include, but are not limited to, phenoxy and naphthoxy.

As used herein, the term “aralkoxy” refers to an optionally substitutedaralkyl-O— group wherein aralkyl is as previously defined. Exemplaryaralkoxy groups include, but are not limited to, benzyloxy,1-phenylethoxy, 2-phenylethoxy, and 3-naphthylheptoxy.

As used herein, the term “aroyl” refers to a carbonyl —C(═O)— group withan aryl moieties wherein aryl is as previously defined. The arylmoieties of aroyl groups can be optionally substituted. Exemplary aroylgroups include, but are not limited to, benzoyl and para-methoxybenzoyl.

As used herein, “carboxy” refers to a —C(═O)OH group.

As used herein, “alkanoyl” refers to a —C(═O)-alkyl group, wherein alkylis as previously defined. In some preferred embodiments the alkylmoieties of the alkanoyl groups have from about 1 to about 5 carbonatoms. In some other preferred embodiments the alkyl moieties of thealkanoyl groups have from about 1 to about 6 carbon atoms. Exemplaryalkanoyl groups include, but are not limited to, acetyl (ethanoyl),n-propanoyl, n-butanoyl, 2-methylpropanoyl, n-pentanoyl,2-methylbutanoyl, 3-methylbutanoyl, 2,2-dimethylpropanoyl, heptanoyl,and decanoyl. Alkanoyl groups can be optionally substituted.

As used herein, “cycloalkanoyl” refers to a —C(═O)-cycloalkyl group,wherein cycloalkyl is as previously defined. In some preferredembodiments the cycloalkyl moieties of the alkanoyl groups have fromabout 3 to about 8 carbon atoms. Exemplary cycloalkanoyl groups include,but are not limited to, cyclohexanoyl, cyclopropanoyl, cyclobutanoyl,2-methylcyclopropanoyl, cyclopentanoyl, cycloheptanoyl, andcyclodecanoyl. Cycloalkanoyl groups can be optionally substituted.

As used herein, “alkoxycarbonyl” refers to a —C(═O)—O-alkyl group,wherein alkyl is as previously defined. In some preferred embodimentsthe alkyl moieties of the alkoxycarbonyl groups have from about 1 toabout 6 carbon atoms. Exemplary alkoxycarbonyl groups include, but arenot limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,i-propoxycarbonyl, n-butoxycarbonyl, and heptoxycarbonyl. Alkoxycarbonylgroups can be optionally substituted.

As used herein, “alkanoyloxy” refers to a —OC(═O)-alkyl group, whereinalkyl is as previously defined. In some preferred embodiments the alkylmoieties of the alkanoyloxy groups have from about 1 to about 5 carbonatoms. Exemplary alkanoyl groups include, but are not limited to,acetoxy (ethanoyloxy), n-propanoyloxy, n-butanoyloxy,2-methylpropanoyloxy, n-pentanoyloxy, 2-methylbutanoyloxy,3-methylbutanoyloxy, 2,2-dimethylpropanoyloxy, heptanoyloxy, anddecanoyloxy. Alkanoyloxy groups can be optionally substituted.

As used herein, “halo” and “halogen” each refers to a fluoro, chloro,bromo, or iodo moiety attached to a compound of the invention.Preferably, “halo” and “halogen” refer to fluoro or chloro moieties.

Typically, substituted chemical moieties include one or moresubstituents that replace hydrogen. Exemplary substituents include, forexample, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl,alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl,heterocycloalkyl, hydroxyl (—OH), nitro (—NO₂), cyano (—CN), amino(—NH₂), —N-substituted amino (—NHR″), —N,N-disubstituted amino(—N(R″)R″), carboxy (—COOH), —O—C(═O)R″, —C(═O)R″, —OR″, —C(═O)OR″,—NHC(═O)R″, aminocarbonyl (—C(═O)NH₂), —N-substituted aminocarbonyl(—C(═O)NHR″), —N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol,thiolato (—SR″), sulfonic acid (—SO₃H), phosphonic acid (—PO₃H),—P(═O)(OR″)OR″, —S(═O)R″, —S(═O)₂R″, —S(═O)₂NH₂, —S(═O)₂ NHR″,—S(═O)₂NR″R″, —NHS(═O)₂R″, —NR″S(═O)₂R″, —CF₃, —CF₂CF₃, —NHC(═O)NHR″,—NHC(═O)NR″R″, —NR″C(═O)NHR″, —NR″C(═O)NR″R″, —NR″C(═O)R″ and the like.In relation to the aforementioned substituents, each moiety R″ can be,independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl,heteroaryl, or heterocycloalkyl, for example.

“Side effect” refers to a consequence other than the one(s) for which anagent or measure is used, as the adverse effects produced by a drug,especially on a tissue or organ system other then the one sought to bebenefited by its administration. In the case, for example, of opioids,the term “side effect” may refer to such conditions as, for example,constipation, nausea and/or vomiting.

“Effective amount” refers to an amount of a compound as described hereinthat may be therapeutically effective to inhibit, prevent or treat thesymptoms of particular disease, disorder or side effect. Such diseases,disorders and side effects include, but are not limited to, thosepathological conditions associated with the administration of opioids(for example, in connection with the treatment and/or prevention ofpain), wherein the treatment or prevention comprises, for example,inhibiting the activity thereof by contacting cells, tissues orreceptors with compounds of the present invention. Thus, for example,the term “effective amount”, when used in connection with opioids, forexample, for the treatment of pain, refers to the treatment and/orprevention of the painful condition. The term “effective amount”, whenused in connection with opioid antagonist compounds, refers to thetreatment and/or prevention of side effects typically associated withopioids including, for example, such side effects as constipation,nausea and/or vomiting, as well as other side effects, discussed infurther detail below.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for contact with the tissues of human beingsand animals without excessive toxicity, irritation, allergic response,or other problem complications commensurate with a reasonablebenefit/risk ratio.

“In combination with”, “combination therapy” and “combination products”refer, in certain embodiments, to the concurrent administration to apatient of opioids and the compounds of formula (I). When administeredin combination, each component may be administered at the same time orsequentially in any order at different points in time. Thus, eachcomponent may be administered separately but sufficiently closely intime so as to provide the desired therapeutic effect.

“Dosage unit” refers to physically discrete units suited as unitarydosages for the particular individual to be treated. Each unit maycontain a predetermined quantity of active compound(s) calculated toproduce the desired therapeutic effect(s) in association with therequired pharmaceutical carrier. The specification for the dosage unitforms of the invention may be dictated by (a) the unique characteristicsof the active compound(s) and the particular therapeutic effect(s) to beachieved, and (b) the limitations inherent in the art of compoundingsuch active compound(s).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. These physiologically acceptable salts are prepared bymethods known in the art, e.g., by dissolving the free amine bases withan excess of the acid in aqueous alcohol, or neutralizing a freecarboxylic acid with an alkali metal base such as a hydroxide, or withan amine.

Compounds described herein throughout, can be used or prepared inalternate forms. For example, many amino-containing compounds can beused or prepared as an acid addition salt. Often such salts improveisolation and handling properties of the compound. For example,depending on the reagents, reaction conditions and the like, compoundsas described herein can be used or prepared, for example, as theirhydrochloride or tosylate salts. Isomorphic crystalline forms, allchiral and racemic forms, N-oxide, hydrates, solvates, and acid salthydrates, are also contemplated to be within the scope of the presentinvention.

Certain acidic or basic compounds of the present invention may exist aszwitterions. All forms of the compounds, including free acid, free baseand zwitterions, are contemplated to be within the scope of the presentinvention. It is well known in the art that compounds containing bothamino and carboxy groups often exist in equilibrium with theirzwitterionic forms. Thus, any of the compounds described hereinthroughout that contain, for example, both amino and carboxy groups,also include reference to their corresponding zwitterions.

“Patient” refers to animals, including mammals, preferably humans.

“Prodrug” refers to compounds specifically designed to maximize theamount of active species that reaches the desired site of reaction,which are of themselves typically inactive or minimally active for theactivity desired, but through biotransformation are converted intobiologically active metabolites.

“Stereoisomers” refers to compounds that have identical chemicalconstitution, but differ as regards the arrangement of the atoms orgroups in space.

“N-oxide” refers to compounds wherein the basic nitrogen atom of eithera heteroaromatic ring or tertiary amine is oxidized to give a quaternarynitrogen bearing a positive formal charge and an attached oxygen atombearing a negative formal charge.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The piperidines of the invention as illustrated in formula I can occuras the trans and cis stereochemical isomers at the 3- and 4-positions ofthe piperidine ring. The term “trans” as used herein refers to theR^(2a) substituent being on the opposite side of the R^(2b) substituent,whereas in the “cis” isomer, the R^(2a) substituent and the R^(2b)substituent are on the same side of the ring. The present inventioncontemplates the individual stereoisomers, as well as racemic mixtures.In the most preferred compounds of the present invention, the R^(2a)substituent and the R^(2b) substituent are in the “trans” orientation onthe piperidine.

In addition to the “cis” and “trans” orientation of the R^(2a)substituent and the R^(2b) substituent, the absolute stereochemistry ofthe carbon atoms bearing the R^(2a) substituent and the R^(2b)substituent is also defined as using the commonly employed “R” and “S”definitions (Orchin et al., The Vocabulary of Organic Chemistry, 1980,John Wiley and Sons, Inc., page 126, which is incorporated herein byreference). The preferred compounds of the present invention are thoseof formula I in which the configuration of both the R^(2a) substituentand the R^(2b) substituent on the piperidine ring is “R”.

Furthermore, asymmetric carbon atoms may be introduced into the moleculedepending on the structure of:

and the independent selection of any variables contained therein. Forexample, when R³ is not hydrogen, the carbon atom to which R³ isattached is asymmetric. Further, independent selection of R⁴ or R⁵, orindependent sub-variables therein contained, may give rise to additionalasymmetric centers. As such, these classes of c5ompounds can exist asthe individual “R” or “S” stereoisomers at each or any of theseasymmetric centers, alone or in combination with any other asymmetriccenters so formed in the compound to provide single enantiomers, or theracemic mixture of the isomers, or diastereomeric mixtures thereof, andall are contemplated as within the scope of the present invention.Preferably, a substantially pure stereoisomer of the compounds of thisinvention is used, i.e., an isomer in which the configuration at each ofthe asymmetric centers is independently “R” or “S”. Preferably, thosestereoisomers are compounds in which the chirality at each of the threeasymmetric carbon centers bearing the R^(2a), R^(2b), and R³ variablesin compounds of formula I is (R).

Other asymmetric centers are contemplated in the present invention. Forexample, in compounds of formula VI, described in further detail below,R⁵ is

In certain preferred embodiments, the compounds, pharmaceuticalcompositions and methods of the present invention may involve aperipheral opioid antagonist compound. The term “peripheral” designatesthat the compound acts primarily on physiological systems and componentsexternal to the central nervous system. In preferred form, theperipheral opioid antagonist compounds employed in the methods of thepresent invention exhibit high levels of activity with respect toperipheral tissue, such as, gastrointestinal tissue, while exhibitingreduced, and preferably substantially no CNS activity. The phrase“substantially no CNS activity,” as used herein, means that less thanabout 20% of the pharmacological activity of the compounds employed inthe present methods is exhibited in the CNS, preferably less than about15%, more preferably less than about 10%, even more preferably less thanabout 5%, and most preferably 0%, of the pharmacological activity of thecompounds employed in the present methods is exhibited in the CNS.

Furthermore, it is preferred in certain embodiments of the inventionwhere the compound is administered to antagonize the peripheral sideeffects of an opioid that the compound does not substantially cross theblood-brain barrier and thereby decrease the beneficial activity of theopioid. The phrase “does not substantially cross,” as used herein, meansthat less than about 20% by weight of the compound employed in thepresent methods crosses the blood-brain barrier, preferably less thanabout 15% by weight, more preferably less than about 10% by weight, evenmore preferably less than about 5% by weight and most preferably 0% byweight of the compound crosses the blood-brain barrier. Selectedcompounds can be evaluated for CNS penetration by determining plasma andbrain levels following i.v. administration.

Accordingly, in one embodiment, the present invention provides novelpharmaceutically active compounds of formula I:

-   -   wherein:        -   R¹ is H or alkyl;        -   R^(2a) is alkyl or alkenyl;        -   R^(2b) is H, alkyl or alkenyl;        -   R³ is H, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,            cycloalkylalkyl, cycloalkenylalkyl, or aralkyl;        -   R⁴ is:            -   H,            -   aryl (optionally substituted by one or more substituents                selected from —OH, nitro, halo, —CN, —CH₂CN, —C(═O)NH₂,                —CO₂H, —N(R^(6a))(R^(6b)), alkoxycarbonyl, aryloxy,                aryl, alkyl, alkoxy, and alkanoyl (which latter three                groups are optionally substituted by one or more halo                atoms)),            -   aralkyl,            -   alkyl,            -   alkenyl, or            -   alkynyl, which latter three groups are optionally                substituted by one or more substituents selected from                —OR^(6c), —S(═O)_(q)R^(6d), —CN, halo, alkoxycarbonyl,                amino, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkanoyl,                —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c), Het¹, and                aryl (which latter group is optionally substituted by                one or more substituents selected from —OH, nitro,                —N(R^(6e))(R^(6b)), halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,                —CHO, aryl, alkyl, alkoxy, aralkoxy, aryloxy, and                alkanoyl (which latter three groups are optionally                substituted by one or more halo atoms));        -   R^(6a), R^(6b), R^(6c), R^(6d), and R^(6e), are each            independently H, Het², alkyl, alkenyl, alkynyl, cycloalkyl,            aralkyl, or aryl (which latter six groups are optionally            substituted by one or more substituents selected from OH,            nitro, halo, —NHC(═O)R³, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,            alkoxycarbonyl, alkyl, alkoxy, and alkanoyl (which latter            three groups are optionally substituted by one or more halo            atoms));        -   R⁵ is (CH₂)_(y)(CHR⁸)_(j)(CHR^(8a))_(z)W,            —CH₂P(═O)OR^(7b)OR^(7c), or —S(═O)₂R^(7d);        -   R⁸ is each independently aryl (optionally substituted by one            or more substituents selected from —OH, nitro, aryl, halo,            —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, —N(R^(6a))(R^(6b)), alkyl,            alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)),            cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl,            alkenyl or alkynyl groups are optionally substituted by one            or more substituents selected from —OR^(6c),            —S(O)_(q)R^(6d), —CN, halo, amino, —CO₂H, —C(═O)NH₂,            alkoxycarbonyl, alkanoyl, alkanoyloxy, cycloalkyl,            cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c),            Het¹, and aryl (which latter group is optionally substituted            by one or more substituents selected from —OH, nitro, amino,            halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, aroyl, aryl, alkyl,            alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)); or R⁴            and R⁸ when taken together with the atoms through which they            are connected, form a 4- to 8-membered heterocycloalkyl            ring, wherein said heterocycloalkyl ring is optionally fused            to an aromatic ring, and wherein said heterocycloalkyl ring,            or the aromatic ring to which it is optionally fused, is            each independently optionally substituted by one or more            substituents selected from —OH, alkyl, or alkoxy; and            wherein the heterocycloalkyl ring is also optionally            interrupted by one or more O, S or N(R¹¹) groups;        -   R^(8a) is each independently H, aryl (optionally substituted            by one or more substituents selected from —OH, nitro, aryl,            halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, —N(R^(6a))(R^(6b)),            alkyl, alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)),            cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl,            alkenyl or alkynyl groups are optionally substituted by one            or more substituents selected from —OR^(6c),            —S(O)_(q)R^(6d), —CN, halo, amino, —CO₂H, —C(═O)NH₂,            alkoxycarbonyl, alkanoyl, alkanoyloxy, cycloalkyl,            cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c),            Het¹, and aryl (which latter group is optionally substituted            by one or more substituents selected from —OH, nitro, amino,            halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, aroyl, aryl, alkyl,            alkoxy, and alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms)); or R⁴            and R^(8a) when taken together with the atoms through which            they are connected, form a 4- to 8-membered heterocycloalkyl            ring, wherein said heterocycloalkyl ring is optionally fused            to an aromatic ring, and wherein said heterocycloalkyl ring,            or the aromatic ring to which is optionally fused, is each            independently optionally substituted by one or more            substituents selected from —OH, alkyl, or alkoxy; and            wherein the heterocycloalkyl ring is also optionally            interrupted by one or more O, S or N(R¹¹) groups;        -   W is —C(═O)OR⁹, —C(═O)N(R^(10a))(R^(10b)), or            —P(═O)OR^(7b)OR^(7c);        -   R⁹ is H, alkyl, alkenyl, phenyl, cycloalkyl, cycloalkenyl,            cycloalkylalkyl, cycloalkenylalkyl, or aralkyl;        -   R^(10a) and R^(10b), each independently represent H, alkyl,            alkenyl, alkynyl, cycloalkyl, aralkyl, Het³, or aryl (which            latter seven groups are optionally substituted by one or            more substituents selected from —OH, nitro, halo, —CN,            —CH₂CN, —C(═O)NH₂, —CO₂H, alkyl, alkoxy, and alkanoyl (which            latter three groups are optionally substituted by one or            more halo atoms)); or R^(10a) and R^(10b) when taken            together with the nitrogen atom to which they are attached            form a 4- to 8-membered heterocycloalkyl ring, wherein said            heterocycloalkyl ring is optionally fused to an aromatic            ring, and wherein said heterocycloalkyl ring, or the            aromatic ring to which it is optionally fused, is each            independently optionally substituted by one or more            substituents selected from —OH, alkyl, or alkoxy; and            wherein the heterocycloalkyl ring is also optionally            interrupted by one or more O, S or N(R¹²) groups;        -   R^(7a), R^(7b), R^(7c), and R^(7d), are each independently            H, alkyl, cycloalkyl, alkaryl, aralkyl or aryl, which latter            five groups are optionally substituted by one or more            substituents selected from alkyl, alkoxy, —OH, nitro, amino            and halo;

Het¹, Het² and Het³ each independently represent a 3- to 8-memberedheterocyclic ring, wherein said heterocyclic ring contains at least oneheteroatom selected from oxygen, sulfur and/or nitrogen, wherein saidheterocyclic ring is optionally fused to an aromatic ring, and whereinsaid heterocyclic ring, or the aromatic ring to which it is optionallyfused, is each independently optionally substituted by one or moresubstituents selected from —OH, ═O, nitro, amino, halo, —CN, —CO₂H,aryl, alkyl, alkoxy and alkanoyl (which latter three groups areoptionally substituted by one or more halo atoms);

-   -   -   R¹¹ represents H, alkyl, cycloalkyl, cycloalkylalkyl, or            aralkyl;        -   R¹² represents H, alkyl, cycloalkyl, cycloalkylalkyl, or            aralkyl;        -   j is the integer 0, 1, 2, 3, or 4;        -   m is the integer 0, 1, 2, 3, or 4;        -   q is the integer 0, 1, or 2;        -   y is the integer 0, 1, 2, 3, 4, or 5; and        -   z is the integer 0, 1, 2, 3, or 4;        -   with the provisos that:            -   when j and z are each the integer 0, y must be the                integer 5; and            -   when R^(8a) is H and j is 0, the sum of y+z must be the                integer 5;

    -   or a stereoisomer, prodrug, pharmaceutically acceptable salt,        hydrate, solvate, acid hydrate, N-oxide or isomorphic        crystalline form thereof.

In certain embodiments of compounds of formula I, R₁ is alkyl or H. Incertain preferred embodiments, R¹ is H.

In other embodiments of compounds of formula I, R^(2a) is alkyl oralkenyl. More preferably, R^(2a) is C₁-C₅ alkyl or C₂-C₆ alkenyl. Morepreferably still, R^(2a) is C₁-C₅ alkyl. Most preferably, R^(2a) ismethyl.

In other embodiments of compounds of formula I, R^(2b) is H, alkyl, oralkenyl. More preferably, R^(2b) is alkyl or alkenyl. More preferablystill, R^(2b) is C₁-C₅ alkyl or C₂-C₆ alkenyl. Even more preferably,R^(2b) is C₁-C₅ alkyl. Most preferably, R^(2b) is methyl.

In certain embodiments of compounds of formula I, R^(2a) and R^(2b) aretrans to each other. More preferably, one or more of R^(2a) and R^(2b)are independently C₁-C₅ alkyl, and R^(2a) and R^(2b) are trans to eachother. More preferably, R^(2a) and R^(2b) are C₁-C₅ alkyl and R^(2a) andR^(2b) are trans to each other. Most preferably, R^(2a) and R^(2b) aremethyl and R^(2a) and R^(2b) are trans to each other.

In other embodiments of compounds of formula I, R³ is H, alkyl, alkenyl,aryl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, oraralkyl. Preferably, R³ is H, alkyl, or aralkyl. In some more preferredembodiments, R³ is H.

In other more preferred embodiments, R³ is aralkyl. Even morepreferably, R³ is benzyl. Most preferably, R³ is:

In other embodiments of the compound of formula I, R⁴ is:

-   -   H,    -   aryl (optionally substituted by one or more substituents        selected from —OH, nitro, halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,        —N(R^(6a))(R^(6b)), alkoxycarbonyl, aryloxy, aryl, alkyl,        alkoxy, and alkanoyl (which latter three groups are optionally        substituted by one or more halo atoms)),    -   aralkyl,    -   alkyl,    -   alkenyl,    -   which latter three groups are optionally substituted by one or        more substituents selected from —OR^(6c), —S(═O)_(q)R^(6d), —CN,        halo, alkoxycarbonyl, amino, alkanoyl, alkanoyloxy, cycloalkyl,        cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c),        Het¹, and aryl (which latter group is optionally substituted by        one or more substituents selected from —OH, nitro, amino,        —N(R^(6a))(R^(6b)), halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, aryl,        alkyl, alkoxy, aralkoxy, aryloxy, and alkanoyl (which latter        three groups are optionally substituted by one or more halo        atoms)).

In some preferred embodiments, R⁴ is H. In other preferred embodiments,R⁴ is:

-   -   aryl (optionally substituted by one or more substituents        selected from alkoxycarbonyl, aryloxy, aryl, and alkoxy (which        latter group is optionally substituted by one or more halo        atoms));    -   aralkyl,    -   alkyl, optionally substituted with cycloalkyl or amino, or    -   alkenyl.

In some other embodiments of the compounds of formula I:

-   -   R^(6a), R^(6b), R^(6c), R^(6d), and R^(6e), are each        independently H, Het², alkyl, alkenyl, alkynyl, cycloalkyl,        aralkyl, or aryl (which latter six groups are optionally        substituted by one or more substituents selected from OH, nitro,        halo, —NHC(═O)R³, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H, alkoxycarbonyl,        alkyl, alkoxy, and alkanoyl (which latter three groups are        optionally substituted by one or more halo atoms));

In certain embodiments of the compounds of formula I, R⁵ is—(CH₂)_(y)(CHR⁸)_(j)(CHR^(8a))_(z)W, —CH₂P(═O)OR^(7b)OR^(7c), or—S(═O)₂R^(7d). In more preferred embodiments, R⁵ is —S(═O)₂R^(7d). Inmore preferred embodiments, R⁵ is —CH₂P(═O)OR^(7b)OR^(7c). In yet othermore preferred embodiments, R⁵ is —(CH₂)_(y)(CHR⁸)_(j)(CHR^(8a))_(z)W.

In some more preferred embodiments, R⁵ is:

In still more preferred embodiments, R⁵ is:

In even more preferred embodiments, R⁵ is:

In some embodiments of the compounds of formula I, each R⁸ isindependently aryl (optionally substituted by one or more substituentsselected from —OH, nitro, aryl, halo, —CN, —CH₂CN, —C(═O)NH₂, —CO₂H,—N(R^(6a))(R^(6b)), alkyl, alkoxy, and alkanoyl (which latter threegroups are optionally substituted by one or more halo atoms)),cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl, alkenyl oralkynyl groups are optionally substituted by one or more substituentsselected from —OR^(6c), —S(O)_(q)R^(6d), —CN, halo, amino, —CO₂H,—C(═O)NH₂, alkoxycarbonyl, alkanoyl, alkanoyloxy, cycloalkyl,cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c), Het¹, andaryl (which latter group is optionally substituted by one or moresubstituents selected from —OH, nitro, amino, halo, —CN, —CH₂CN,—C(═O)NH₂, —CO₂H, aroyl, aryl, alkyl, alkoxy, and alkanoyl (which latterthree groups are optionally substituted by one or more halo atoms)). Insome preferred embodiments, each R⁸ is independently aryl, cycloalkyl,alkyl, wherein the alkyl group is optionally substituted by one or moresubstituents selected from —OR^(6c), —S(O)_(q)R^(6d), amino, —CO₂H,—C(═O)NH₂, cycloalkyl, —N(R^(6e))S(═O)₂R^(7a), Het¹, and aryl (whichlatter group is optionally substituted by one or more substituentsselected from —OH, nitro, halo, aroyl, and aryl. In certain morepreferred embodiments, R⁸ is alkyl substituted with aryl in which thearyl is optionally substituted by one or more substituents selected from—OH, nitro, fluoro, iodo, benzoyl, and phenyl). In even more preferredembodiments, R⁸ is methyl or ethyl, substituted with phenyl, α-naphthyl,or β-naphthyl, the latter three groups optionally substituted by one ormore substituents selected from —OH, nitro, fluoro, iodo, benzoyl, andphenyl).

In some other embodiments of the compounds of formula I, R⁴ and R⁸ whentaken together with the atoms through which they are connected, form a4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkylring is optionally fused to an aromatic ring, and wherein theheterocycloalkyl ring, or the aromatic ring to which it is optionallyfused, is each independently optionally substituted by one or moresubstituents selected from —OH, alkyl, or alkoxy; and wherein theheterocycloalkyl ring is also optionally interrupted by one or more O, Sor N(R¹¹) groups. In certain preferred embodiments, R⁴ and R⁸ when takentogether with the atoms through which they are connected, form a 5- to6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring isoptionally fused to an aromatic ring, and wherein said heterocycloalkylring, or the aromatic ring to which it is optionally fused, is eachindependently optionally substituted by one or more substituentsselected from —OH, alkyl, or alkoxy; and wherein the heterocycloalkylring is also optionally interrupted by one or more O, S or N(R¹¹)groups. In other preferred embodiments, R⁴ and R⁸ when taken togetherwith the atoms through which they are connected, form a 5-memberedheterocycloalkyl ring wherein the heterocycloalkyl ring is optionallysubstituted by —OH. In other preferred embodiments, R⁴ and R⁸ when takentogether with the atoms through which they are connected, form a 6membered heterocycloalkyl ring wherein the heterocycloalkyl ring isfused to an aromatic ring.

In certain embodiments of the compounds of formula I, each R^(8a) isindependently H, aryl (optionally substituted by one or moresubstituents selected from —OH, nitro, aryl, halo, —CN, —CH₂CN,—C(═O)NH₂, —CO₂H, —N(R^(6a))(R^(6b)), alkyl, alkoxy, and alkanoyl (whichlatter three groups are optionally substituted by one or more haloatoms)), cycloalkyl, alkyl, alkenyl or alkynyl wherein said alkyl,alkenyl or alkynyl groups are optionally substituted by one or moresubstituents selected from —OR^(6c), —S(O)_(q)R^(6d), —CN, halo, amino,—CO₂H, —C(═O)NH₂, alkoxycarbonyl, alkanoyl, alkanoyloxy, cycloalkyl,cycloalkanoyl, —N(R^(6e))S(═O)₂R^(7a), —P(═O)OR^(7b)OR^(7c), Het¹, andaryl (which latter group is optionally substituted by one or moresubstituents selected from —OH, nitro, amino, halo, —CN, —CH₂CN,—C(═O)NH₂, —CO₂H, aroyl, aryl, alkyl, alkoxy, and alkanoyl (which latterthree groups are optionally substituted by one or more halo atoms)); orR⁴ and R^(8a) when taken together with the atoms through which they areconnected, form a 4- to 8-membered heterocycloalkyl ring, wherein saidheterocycloalkyl ring is optionally fused to an aromatic ring, andwherein said heterocycloalkyl ring, or the aromatic ring to which isoptionally fused, is each independently optionally substituted by one ormore substituents selected from —OH, alkyl, or alkoxy; and wherein theheterocycloalkyl ring is also optionally interrupted by one or more O, Sor N(R¹¹) groups.

In certain embodiments of the compounds of formula I, W is —C(═O)OR⁹,—C(═O)N(R^(10a))(R^(10b)), or —P(═O)OR^(7b)OR^(7c). In certain preferredembodiments, W is —C(═O)OR⁹. More preferably, when W is —C(═O)OR⁹, R⁹ isH. In certain other preferred embodiments, W is—C(═O)N(R^(10a))(R^(10b)). In some other preferred embodiments, W is—P(═O)OR^(7b)OR^(7c). More preferably, when W is —P(═O)OR^(7b)OR^(7c),R^(7b) and R^(7c) are both H.

In certain embodiments of the compounds of formula I, R⁹ is H, alkyl,alkenyl, phenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl), or aralkyl. Preferably, R⁹ is H.

In other embodiments of the compounds of formula I, R^(10a) and R^(10b),each independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl,aralkyl, Het³, or aryl (which latter seven groups are optionallysubstituted by one or more substituents selected from —OH, nitro, halo,—CN, —CH₂CN, —C(═O)NH₂, —CO₂H, alkyl, alkoxy, and alkanoyl (which latterthree groups are optionally substituted by one or more halo atoms)); orR^(10a) and R^(10b) when taken together with the nitrogen atom to whichthey are attached form a 4- to 8-membered heterocycloalkyl ring whereinsaid heterocycloalkyl ring is optionally fused to an aromatic ring, andwherein said heterocycloalkyl ring, or the aromatic ring to which it isoptionally fused, is each independently optionally substituted by one ormore substituents selected from —OH, alkyl, or alkoxy; and wherein theheterocycloalkyl ring is also optionally interrupted by one or more O, Sor N(R¹²) groups. More preferably, R^(10a) and R^(10b) are each selectedindependently from H and alkyl, wherein the alkyl is optionallysubstituted by one or more halo atoms.

In some embodiments of the compounds of formula I, R^(7a), R^(7b),R^(7c), and R^(7d) are each independently H, alkyl, cycloalkyl, alkaryl,aralkyl, or aryl, which latter five groups are optionally substituted byone or more substituents selected from alkyl, alkoxy, —OH, nitro, aminoand halo. In some preferred embodiments, one or more R^(7b) and R^(7c)are each independently H. More preferably, R^(7b) and R^(7c) are both H.In other embodiments, R^(7d) is alkyl, optionally substituted by one ormore halo atoms. More preferably, R^(7d) is alkyl, optionallysubstituted by one or more fluoro atoms. Still more preferably, R^(7d)is —CF₃.

In other embodiments of the compounds of formula I, Het¹, Het² and Het³each independently represent a 3- to 8-membered heterocyclic ring,wherein said heterocyclic ring contains at least one heteroatom selectedfrom oxygen, sulfur and/or nitrogen, wherein said heterocyclic ring isoptionally fused to an aromatic ring, and wherein said heterocyclicring, or the aromatic ring to which it is optionally fused, is eachindependently optionally substituted by one or more substituentsselected from —OH, ═O, nitro, amino, halo, —CN, —CO₂H, aryl, alkyl,alkoxy and alkanoyl (which latter three groups are optionallysubstituted by one or more halo atoms). In certain preferredembodiments, Het¹ is:

In still other embodiments of the compounds of formula I, R¹¹ representsH, alkyl, cycloalkyl, cycloalkylalkyl or aralkyl.

In yet other embodiments of the compounds of formula I, R¹² representsH, alkyl, cycloalkyl, cycloalkylalkyl or aralkyl.

In still other embodiments of the compounds of formula I, j is theinteger 0, 1, 2, 3, or 4; m is the integer 0, 1, 2, 3, or 4; q is theinteger 0, 1, or 2; y is the integer 0, 1, 2, 3, 4, or 5; and z is theinteger 0, 1, 2, 3, or 4; with the provisos that when j and z are eachthe integer 0, y must be the integer 5; and when R^(8a) is H and j is 0,the sum of y+z must be the integer 5. In certain preferred embodiments,j is the integer 1. In certain other preferred embodiments, m is theinteger 1. In still other preferred embodiments, y is the integer 5.

In certain preferred embodiments of the present invention, the compoundsof formula I have the structure corresponding to formula II:

wherein R¹, R^(2a), R^(2b), R³, R⁴, R⁵, and m are as set forth above. Inmore preferred embodiments, R^(2a) and R^(2b) are each methyl.

Alternatively, the compounds of formula I have the structurecorresponding to formula III:

wherein R³ is H, alkyl, or aralkyl, and R⁴ and R⁵ are as set forthabove.

In certain embodiments, the compounds of formula I have the structurecorresponding to formula IV:

wherein R³ is H, alkyl, or aralkyl, and R^(2a), R^(2b), R⁴, R⁸, R^(8a),W, y, j, and z are as set forth above. In some preferred embodiments ofcompounds of formula IV, R⁴ is H. In other preferred embodiments ofcompounds of formula IV, R³ is:

In certain other embodiments, the compounds of formula I have thestructure corresponding to formula V:

wherein R³ is H, alkyl, or aralkyl, and R^(2a), R^(2b), R⁴, R⁸, and Ware as set forth above. In some preferred embodiments of compounds ofthe formula V, R⁴ is H. In other preferred embodiments, the compounds ofthe formula V have the structure corresponding to formula VIa or formulaVIb:

wherein R³ is H, alkyl, or aralkyl, and R^(2a), R^(2b), R⁸, and W are asset forth above. In some preferred embodiments of compounds of formulaVIa and formula VIb, W is —CO²H, and R^(2a) and R^(2b) are each methyl.In certain more preferred embodiments of the compounds of formula VIaand formula VIb, wherein W is —CO²H, and R^(2a) and R^(2b) are eachmethyl, R³ is:

In certain more preferred embodiments of compounds of formula VIa andformula VIb, wherein W is —CO²H, and R^(2a) and R^(2b) are each methyl,and R³ is:

R⁴ is H.

In other more preferred embodiments of compounds of formula VI, whereinW is —CO²H, and R^(2a) and R^(2b) are each methyl, R⁸ is alkylsubstituted with aryl, optionally substituted by one or moresubstituents selected from —OH, nitro, amino, halo, —CN, —CH₂CN,—C(═O)NH₂, —CO₂H, aroyl, aryl, —N(R^(6a))(R^(6b)), alkyl, alkoxy, andalkanoyl (which latter three groups are optionally substituted by one ormore halo atoms). Even more preferably, R⁸ is optionally substitutedbenzyl. Even more preferably, said benzyl is substituted by one or moresubstituents selected from —OH, nitro, halo, aroyl, or aryl.

In certain preferred embodiments, the compounds of formula V have thestructure corresponding to formula VII:

wherein R^(2a), R^(2b), R³, R⁴, and R⁸ are as set forth above. In morepreferred compounds of formula VII, R³ is:

Even more preferably, in compounds of formula VII, R^(2a) and R^(2b) areeach methyl, and R³ is as set forth directly above. More preferablystill, the compounds of formula VII have the structure corresponding toformula VIIa or formula VIIb:

In certain preferred embodiments of the present invention, the compoundsof formula I have the structure corresponding to formula VIII:

wherein R³ is H, alkyl, or aralkyl, and R^(2a), R^(2b), R⁴, and R^(7d)are as set forth above.

In certain preferred embodiments of the present invention, the compoundsof formula I have the structure corresponding to formula IX:

wherein R³ is H, alkyl, or aralkyl, and R^(2a), R^(2b), R⁴, R^(7b)andR^(7c) are as set forth above.

The compounds employed in the methods of the present invention may existin prodrug form. As used herein, “prodrug” is intended to include anycovalently bonded carriers which release the active parent drug, forexample, as according to formula I or other formulas or compoundsemployed in the methods of the present invention in vivo when suchprodrug is administered to a mammalian subject. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds employedin the present methods may, if desired, be delivered in prodrug form.Thus, the present invention contemplates methods of delivering prodrugs.Prodrugs of the compounds employed in the present invention, for exampleformula I, may be prepared by modifying functional groups present in thecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds can be synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

As discussed in detail above, compounds employed in the present methodsmay contain one or more asymmetrically substituted carbon atoms, and maybe isolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare and isolate such optically active forms. For example, mixturesof stereoisomers may be separated by standard techniques including, butnot limited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxy groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred protecting groups includethe benzyloxycarbonyl group and the tert-butyloxycarbonyl group. Otherpreferred protecting groups that may be employed in accordance with thepresent invention may be described in Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis 3d. Ed., Wiley & Sons, 1991.

The 3,4-disubstituted-4-aryl piperidine compounds according to thepresent invention may be synthesized employing methods taught, forexample, in U.S. Pat. No. 5,250,542, U.S. Pat. No. 5,434,171, U.S. Pat.No. 5,159,081, and U.S. Pat. No. 5,270,328, the disclosures of which arehereby incorporated herein by reference in their entireties. Theoptically active (+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinewas employed as starting material in the synthesis of the presentcompounds may be prepared by the general procedure taught in J. Org.Chem., 1991, 56, 1660-1663, U.S. Pat. No. 4,115,400 and U.S. Pat. No.4,891,379, the disclosures of which are hereby incorporated herein byreference in their entireties.

While not intending to be bound by any theory or theories of operation,it is contemplated that opioid side effects, such as constipation,vomiting and nausea, may result from undesirable interaction of theopioid with peripheral opioid receptors, such as peripheral μ receptors.Administration of the compounds of formula I according to one aspect ofthe present invention may block interaction of the opioid compounds withthe peripheral receptors, thereby preventing and/or inhibiting the sideeffects, while preferably not interfering with the therapeutic effect ofthe opioid in the CNS.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

In accordance with certain embodiments of the present invention, thereare provided methods that comprise administering to a patient, interalia, an opioid compound. A wide variety of opioids is available thatmay be suitable for use in the present methods and compositions.Generally speaking, it is only necessary that the opioid provide thedesired effect (for example, pain alleviation), and be capable of beingincorporated into the present combination products and methods(discussed in detail below). In preferred embodiments, the presentmethods and compositions may involve an opioid that is selected fromalfentanil, buprenorphine, butorphanol, codeine, dezocine,dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and/ortramadol. More preferably, the opioid is selected from morphine,codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl,tramadol, and mixtures thereof.

The opioid component of the present compositions may further include oneor more other active ingredients that may be conventionally employed inanalgesic and/or cough-cold-antitussive combination products. Suchconventional ingredients include, for example, aspirin, acetaminophen,phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/orguaifenesin. Typical or conventional ingredients that may be included inthe opioid component are described, for example, in the Physicians' DeskReference, 1999, the disclosure of which is hereby incorporated hereinby reference, in its entirety.

In addition, the opioid component may further include one or morecompounds that may be designed to enhance the analgesic potency of theopioid and/or to reduce analgesic tolerance development. Such compoundsinclude, for example, dextromethorphan or other NMDA antagonists (Mao,M. J. et al., Pain, 1996, 67, 361), L-364,718 and other CCK antagonists(Dourish, C. T. et al., Eur. J. Pharmacol., 1988, 147, 469), NOSinhibitors (Bhargava, H. N. et al., Neuropeptides, 1996, 30, 219), PKCinhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther., 1996, 277,484), and dynorphin antagonists or antisera (Nichols, M. L. et al.,Pain, 1997, 69, 317). The disclosures of each of the foregoing documentsare hereby incorporated herein by reference, in their entireties.

Other opioids, optional conventional opioid components, and optionalcompounds for enhancing the analgesic potency of the opioid and/or forreducing analgesic tolerance development, that may be employed in themethods and compositions of the present invention, in addition to thoseexemplified above, would be readily apparent to one of ordinary skill inthe art; once armed with the teachings of the present disclosure.

Another embodiment of the invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I.

Yet another embodiment of the invention provides a method for treatingor preventing opioid-bowel dysfunction comprising the step ofadministering to a patient in need of such treatment a compositioncomprising an opioid and an effective amount of a compound of formula I.

Still another embodiment of the invention provides a method for treatingor preventing ileus comprising the step of administering to a patient inneed of such treatment, an effective amount of a compound of formula I.

Another embodiment of the invention provides a method for treating orpreventing a side effect associated with an opioid comprising the stepof administering to a patient, an effective amount of a compound offormula I.

Although the compounds of the present invention may be administered asthe pure chemicals, it is preferable to present the active ingredient asa pharmaceutical composition. The invention thus further provides apharmaceutical composition comprising one or more of the compounds offormula I, together with one or more pharmaceutically acceptablecarriers therefore and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the composition andnot deleterious to the recipient thereof.

The compounds of the invention may be administered in an effectiveamount by any of the conventional techniques well-established in themedical field. The compounds employed in the methods of the presentinvention including, for example, opioid and the compounds of formula I,may be administered by any means that results in the contact of theactive agents with the agents' site or site(s)of action in the body of apatient. The compounds may be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.For example, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

The compounds are preferably combined with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice as described, for example, in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980), thedisclosures of which are hereby incorporated herein by reference, intheir entirety.

Compounds of the present invention can be administered to a mammalianhost in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepithelial including transdermal, ophthalmic, sublingual andbuccal; topically including ophthalmic, dermal, ocular, rectal and nasalinhalation via insufflation, aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The amount of active compound(s) in such therapeuticallyuseful compositions is preferably such that a suitable dosage will beobtained. Preferred compositions or preparations according to thepresent invention may be prepared so that an oral dosage unit formcontains from about 0.1 to about 1000 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain oneor more of the following: a binder, such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent, such as corn starch, potato starch, alginic acidand the like; a lubricant, such as magnesium stearate; a sweeteningagent such as sucrose, lactose or saccharin; or a flavoring agent, suchas peppermint, oil of wintergreen or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form ispreferably pharmaceutically pure and substantially non-toxic in theamounts employed. In addition, the active compound may be incorporatedinto sustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also be prepared in glycerol, liquid polyethylene glycols, andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations may contain a preservative to prevent the growthof microorganisms.

The pharmaceutical forms suitable for injectable use include, forexample, sterile aqueous solutions or dispersions and sterile powdersfor the extemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form is preferably sterile and fluid toprovide easy syringability. It is preferably stable under the conditionsof manufacture and storage and is preferably preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier may be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating, such as lecithin, by the maintenance of therequired particle size in the case of a dispersion, and by the use ofsurfactants. The prevention of the action of microorganisms may beachieved by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.In many cases, it will be preferable to include isotonic agents, forexample, sugars or sodium chloride. Prolonged absorption of theinjectable compositions may be achieved by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the activecompounds in the required amounts, in the appropriate solvent, withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions may be prepared byincorporating the sterilized active ingredient into a sterile vehiclewhich contains the basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, the preferredmethods of preparation may include vacuum drying and the freeze dryingtechnique that yields a powder of the active ingredient, plus anyadditional desired ingredient from the previously sterile-filteredsolution thereof.

The therapeutic compounds of this invention may be administered to apatient alone or in combination with a pharmaceutically acceptablecarrier. As noted above, the relative proportions of active ingredientand carrier may be determined, for example, by the solubility andchemical nature of the compounds, chosen route of administration andstandard pharmaceutical practice.

The dosage of the compounds of the present invention that will be mostsuitable for prophylaxis or treatment will vary with the form ofadministration, the particular compound chosen and the physiologicalcharacteristics of the particular patient under treatment. Generally,small dosages may be used initially and, if necessary, increased bysmall increments until the desired effect under the circumstances isreached. Generally speaking, oral administration may require higherdosages.

The combination products of this invention, such as pharmaceuticalcompositions comprising opioids in combination with the compounds offormula I, may be in any dosage form, such as those described herein,and can also be administered in various ways, as described herein. In apreferred embodiment, the combination products of the invention areformulated together, in a single dosage form (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.). When the combinationproducts are not formulated together in a single dosage form, the opioidcompounds and the compounds of formula I may be administered at the sametime (that is, together), or in any order. When not administered at thesame time, preferably the administration of an opioid and the compoundsof formula I occurs less than about one hour apart, more preferably lessthan about 30 minutes apart, even more preferably less than about 15minutes apart, and still more preferably less than about 5 minutesapart. Preferably, administration of the combination products of theinvention is oral, although other routes of administration, as describedabove, are contemplated to be within the scope of the present invention.Although it is preferable that the opioids and the compounds of formulaI are both administered in the same fashion (that is, for example, bothorally), if desired, they may each be administered in different fashions(that is, for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously). The dosage of the combination products of the inventionmay vary depending upon various factors such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the kind of concurrent treatment, thefrequency of treatment, and the effect desired.

Although the proper dosage of the combination products of this inventionwill be readily ascertainable by one skilled in the art, once armed withthe present disclosure, by way of general guidance, where an opioidcompounds is combined with the compounds of formula I, for example,typically a daily dosage may range from about 0.01 to about 100milligrams of the opioid (and all combinations and subcombinations ofranges therein) and about 0.001 to about 100 milligrams of the compoundsof formula I (and all combinations and subcombinations of rangestherein), per kilogram of patient body weight. Preferably, the a dailydosage may be about 0.1 to about 10 milligrams of the opioid and about0.01 to about 10 milligrams of the compounds of formula I per kilogramof patient body weight. Even more preferably, the daily dosage may beabout 1.0 milligrams of the opioid and about 0.1 milligrams of thecompounds of formula I per kilogram of patient body weight. With regardto a typical dosage form of this type of combination product, such as atablet, the opioid compounds (e.g., morphine) generally may be presentin an amount of about 15 to about 200 milligrams, and the compounds offormula I in an amount of about 0.1 to about 4 milligrams.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients (forexample, an opioid and the compounds of formula I). For this reason, thepreferred dosage forms of the combination products of this invention areformulated such that although the active ingredients are combined in asingle dosage form, the physical contact between the active ingredientsis minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneor more of the active ingredients, it is possible not only to minimizethe contact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material that effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in, for example, the treatment of pain, whichcomprise a therapeutically effective amount of an opioid along with atherapeutically effective amount of the3,4-disubstituted-4-aryl-piperidine compound of the invention, in one ormore sterile containers, are also within the ambit of the presentinvention. Sterilization of the container may be carried out usingconventional sterilization methodology well known to those skilled inthe art. The sterile containers of materials may comprise separatecontainers, or one or more multi-part containers, as exemplified by theUNIVIAL™ two-part container (available from Abbott Labs, Chicago, Ill.),as desired. The opioid compound and the compounds of formula I may beseparate, or combined into a single dosage form as described above. Suchkits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as for example, one ormore pharmaceutically acceptable carriers, additional vials for mixingthe components, etc., as will be readily apparent to those skilled inthe art. Instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, may also beincluded in the kit.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The dose may also be provided by controlled release of the compound, bytechniques well known to those in the art.

The compounds of the present invention may be used in methods to bindopioid receptors, including μ and κ opioid receptors. Such binding maybe accomplished by contacting the receptor with an effective amount ofthe compound of the invention. Preferably, the contacting step conductedin an aqueous medium, preferably at physiologically relevant ionicstrength, pH, and the like.

In certain preferred embodiments, the compounds of the present inventionbind μ and κ opioid receptors or combinations thereof. The opioidreceptors may be located in the central nervous system or locatedperipherally to the central nervous system or in both locations.

In certain other preferred embodiments, the compounds of the presentinvention bind κ opioid receptors.

In preferred embodiments of the methods of the invention, the compoundsantagonize the activity of the opioid receptors. In other preferredembodiments, the compounds prevent or treat a condition or diseasecaused by an opioid (either endogenous or exogenous). In certainembodiments of the method, particularly where the opioid are exogenous,the compounds of the invention preferably do not substantially cross theblood-brain barrier.

The compounds of the present invention may be used in methods toantagonize μ, κ or both types of opioid receptors, particularly whereundesirable symptoms or conditions are side effects of administeringexogenous opioids. Furthermore, the compounds of the invention may beused as to treat patients having disease states that are ameliorated bybinding opioid receptors or in any treatment wherein temporarysuppression of the μ, κ or both types of opioid receptor system isdesired.

Such symptoms, conditions or diseases include the complete or partialantagonism of opioid-induced sedation, confusion, respiratorydepression, euphoria, dysphoria, hallucinations, pruritus (itching),increased biliary tone, increased biliary colic, and urinary retention,ileus, emesis, and addiction liability; prevention or treatment ofopioid and cocaine dependence; rapid opioid detoxification; treatment ofalcoholism; treatment of alcoholic coma; detection of opioid use orabuse (pupil test); treatment of eating disorders; treatment of obesity;treatment of post-concussional syndrome; adjunctive therapy in septic,hypovolemic or endotoxin-induced shock; potentiation of opioid analgesia(especially at ultra-low doses); reversal or prevention of opioidtolerance and physical dependence (especially at ultra-low doses);prevention of sudden infant death syndrome; treatment of psychosis(especially wherein the symptoms are associated with schizophrenia,schizophreniform disorder, schizoaffective disorder, unipolar disorder,bipolar disorder, psychotic depression, Alzheimer's disease, Parkinson'sdisease, compulsive disorders, and other psychiatric or neurologicdisorders with psychosis as symptoms); treatment of dyskinesia,treatment of autism; treatment of the endocrine system (includingincreased release of leutinizing hormone, treatment of infertility,increasing number of multiple births in animal husbandry, and male andfemale sexual behavior); treatment of the immune system and cancersassociated with binding of the opioid receptors; treatment ofanxiolysis; treatment of diuresis; treatment and regulation of bloodpressure; treatment of tinnitus or impaired hearing; treatment ofepilepsy; treatment of cachexia; treatment of general cognitivedysfunctions; and treatment of kleptomania.

The compounds of the invention present invention may also be used ascytostatic agents, as antimigraine agents, as immunomodulators, asimmunosuppressives, as antiarthritic agents, as antiallergic agents, asvirucides, to treat diarrhea, antipsychotics, as antischizophrenics, asantidepressants, as uropathic agents, as antitussives, as antiaddictiveagents, as anti-smoking agents, to treat alcoholism, as hypotensiveagents, to treat and/or prevent paralysis resulting from traumaticischemia, general neuroprotection against ischemic trauma, as adjunctsto nerve growth factor treatment of hyperalgesia and nerve grafts, asanti-diuretics, as stimulants, as anti-convulsants, or to treat obesity.Additionally, the present compounds may be used in the treatment ofParkinson's disease as an adjunct to L-dopa for treatment dyskinesiaassociated with the L-dopa treatment.

In certain preferred embodiments, the compounds of the invention may beused in methods for preventing or treating gastrointestinal dysfunction,including, but not limited to, irritable bowel syndrome, opioid-boweldysfunction, colitis, post-operative and opioid-induced emesis (nauseaand vomiting), decreased gastric motility and emptying, inhibition ofsmall and/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, and delayed absorptionof orally administered medications or nutritive substances.

In certain preferred embodiments, the compounds of the invention may beused in methods for preventing or treating post-operative oropioid-induced ileus.

In other preferred embodiments, the compounds of the invention may beused in an effective amount in a method in combination with an effectiveamount of an opioid to treat pain.

The compounds of the invention may be administered before, during orafter administering at least one opioid. The methods of the inventionare particularly effective for opioids selected from alfentanil,buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine,propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

Employing the methodology herein described or cited,N-substituted-(3-substituted phenyl)-3,4-disubstituted-1-piperidinecompounds of formula I can be readily prepared. The invention is furtherdescribed in the following examples. The actual examples, hereinprovided, are for illustrative purposes only, and are not to beconstrued as limiting the appended claims. They provide a series ofN-substituted (+)-4(R)-(3-substitutedphenyl)-3(R),4-dimethyl-1-piperidine derivatives of Formulae V and VII,prepared according to Schemes 1-5, shown below.

The Examples 1 and 6 to 36 listed in Table 1 were prepared according tothe Scheme 1. Fmoc-protected α-amino acids linked to Wang resin (1),purchased from Advanced Chemtech, were used as starting material for thesynthesis of derivatives of general formula 5. Treatment of 1 withpiperidine/DMF afforded the resin-bound Fmoc deprotected α-amino acids 2which were coupled to the acid 3 [Werner et al., J. Org. Chem, 1996, 61,587-597] using HATU as coupling agent. The reaction time (3 hours) andnumber of equivalents of each reagent were critical in order to obtaingood conversion of the desired coupled product 4 while minimizing theformation of the O-acylation side products. Cleavage of the resin 4using trifluoroacetic acid gave the desired carboxylic acid derivatives.Under the acidic cleavage conditions, all Boc, tert-butyl, and tritylprotecting groups (R1 substituents) were simultaneously removed togenerate the corresponding primary or secondary amines, carboxylicacids, alcohols, indoles, imidazoles, and carboxamides. The purity ofcleaved products was generally >50% as determined by LCMS and compoundswere purified to >98% purity by routine HPLC.

Alternatively, the Fmoc-protected α-amino acids may be prepared by knowntechniques (such as those disclosed in Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis 3d. Ed., Wiley & Sons, 1999) andthen attached to the Wang resin using standard coupling procedures (suchas those disclosed in Bryan et al., Tetrahedron Letters, 2000, 41,6997-7000; Burkett et al., Tetrahedron Letters, 2000, 41, 6661-6664.

The derivatives of general formula 9 (Examples 2 and 37 to 66) wereprepared by a procedure (Scheme 2) analogous to that shown in Scheme 1.Coupling of 2 with the carboxylic acid 7, obtained by hydrolysis underbasic conditions of the methyl ester 6 [Werner et al., J. Org. Chem,1996, 61, 587-597], afforded the resin 8 which was cleaved usingtrifluoroacetic acid to give the carboxylic acid derivatives 9. Asmentioned previously, under the acidic cleavage conditions, all Boc,tert-butyl and trityl protecting groups were simultaneously removed togenerate the corresponding primary or secondary amines, carboxylicacids, alcohols, indoles, imidazoles and carboxamides. The purity ofcleaved products was generally >50% as determined by LCMS and compoundswere purified to >98% purity by routine HPLC.

The derivatives of general formula 14 (Examples 3, 67-70) were preparedaccording to Scheme 3. The reductive amination of the primary amine ofthe α-amino acid linked to Wang resin (2), using previously reportedstrategy [ Matthews et al. J. Org. Chem, 1997, 62, 6090-6092] providedthe secondary amine intermediates 10. Coupling of resins 10 withacryloyl chloride in the presence of triethylamine provided theresin-bound acrylamide derivatives 11 which reacted with(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) [J. Org.Chem., 1991, 56, 1660-1663] to give the desired 1,4-addition products13. The resin intermediates 13 were cleaved using trifluoroacetic acidto give the carboxylic acid derivatives 14. The purity of cleavedproducts was generally >50% as determined by LCMS and compounds werepurified to >98% purity by routine preparative HPLC.

The derivatives of general formula 20 (Examples 4, 71-78) were preparedaccording to the Scheme 4. The secondary amine derivatives 17 wereobtained using a solid-phase variant of the Fukuyama-Mitsunobu process[Piscopio et al. Tetrahedron Lett., 1998, 39, 2667-2670; Piscopio et al.Tetrahedron, 1999, 55, 8189-8198; Yang et al. Tetrahedron Lett., 1997,38, 7307-7310]. Hence, 2,4-dinitrosulfonamides 15, prepared from resin 2and 2,4-dinitrobenzenesulfonyl chloride, can be alkylated efficientlyunder the Mitsunobu conditions (ROH, DIAD, Ph₃P, THF) to give theN,N-disubstituted 2,4-dinitrobenzenesulfonamides 16. Facile deprotectionof 16 using n-butylamine provided the secondary amine intermediates 17.Coupling of resins 17 with acryloyl chloride in the presence ofdiisopropylethylamine provided the resin-bound acrylamide derivatives 18that reacted with(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) to give the1,4-addition products 19. The resin intermediates 19 were cleaved usingtrifluoroacetic acid to give the carboxylic acid derivatives 20. Thepurity of cleaved products was generally >50% as determined by LCMS andcompounds were purified to >98% purity by routine HPLC.

The derivatives of general formula 24 (Examples 5, 79, 80) were preparedaccording to the Scheme 5. The N-arylation of the resin-bound Fmocdeprotected α-amino acids 2 was conducted according to the methoddescribed by Combs and collaborators [Combs et al., J. Comb. Chem. 2002,4, 179-182] (ArB(OH)₂, Cu(OAc)₂, Et₃N, THF). Coupling of the resultingresins 21 with acryloyl chloride in the presence of triethylamineprovided the resin-bound acrylamide derivatives 22 which reacted with(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) to give the1,4-addition products 23. The resin intermediates 23 were cleaved usingtrifluoroacetic acid to give the carboxylic acid derivatives 24. Theinitial purity of final products was generally >50% as determined byLCMS and compounds were purified to >98% purity by routine HPLC.

(1) Experimental Section

Materials: all chemicals were reagent grade and used without furtherpurification. LC-MS data were obtained using a LC Thermo FinniganSurveyor-MS Thermo Finnigan AQA in either positive mode or negativemode. Solvent A: 10 mM ammonium acetate, pH 4.5; solvent B:acetonitrile; solvent C: methanol; solvent D: water; column WatersXterra C18 MS 2.0×50 mm, detector: PDA λ=220-300 nM. Gradient program(positive mode): t=0.00, 600 μL/min, 99% A-1% B; t=0.30, 600 μL/min, 99%A-1% B; t=5.00, 600 μL/min, 1% A-99% B; t=5.30, 600 μL/min, 1% A-99% B.Gradient program (negative mode): t=0.00, 600 μL/min, 9% A-1% B-90% D;t=0.30, 600 μL/min, 9% A-1% B-90% D; t=5.00, 600 μL/min, 99% B-1% D;t=5.30, 600 μL/min, 99% B-1% D.

Example 12(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-phenyl-propionicacid (5a)

A solution dimethylformamide/piperidine 20:80 (20 mL) was added to theFmoc-Phe Wang resin 1a (0.8 mmol/g, 0.250 g, 0.0002 mol) and thesuspension was mixed at room temperature for 20 minutes (Scheme 1). Theresin was then drained, washed consecutively with dimethylformamide(5×), dimethylformamide/water (9:1) (5×), dimethylformamide (5×),methanol (5×), dichloromethane (5×), diethyl ether (5×) and dried undervacuum. To a suspension of the resulting resin 2a in a mixturedichloromethane/dimethylformamide 1:1 (20 mL) was added consecutivelydiisopropylethylamine (0.036 mL, 0.00021 mol, 1.05 eq), carboxylic acid3 (0.081 g, 0.00021 mol, 1.05 eq), and HATU (0.080 g, 0.00021 mol, 1.05eq). The mixture was shaken for 3 h at room temperature. The resin wasthen drained, washed consecutively with dimethylformamide (5×),dimethylformamide/water(9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum.The resin 4a was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (10 mL) at room temperature for 20 min. Thefiltrate was collected and the resin was further washed withdichloromethane (3×2 mL). Evaporation of the filtrate afforded thedesired compound further purified by routine HPLC. For Example 1 (5a),R⁸═(S) CH₂Ph; Mass spectral analysis: m/z=515 (M+H)⁺.

Example 22(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-phenyl-propionicacid (9a)

Preparation of Carboxylic Acid Derivative 7:

A 1N solution of aqueous sodium hydroxide (58.2 mL, 0.05821 mol, 3 eq)was added drop wise to a cold (0° C.) solution of 6 (5.65 g, 0.01940mol, 1 eq) in tetrahydrofuran (100 mL). The mixture was allowed to warmto room temperature and stirring was continued for 16 h at roomtemperature. A 12N aqueous HCl solution (4.85 mL, 0.0582 mol, 3 eq) wasadded to neutralize the mixture that was concentrated under vacuum. Theresulting solid was suspended in a mixture dichloromethane/MeOH 98:2.The mixture was filtered and the filtrate was evaporated to afford thedesired compound 7 (3.7 g, 69%) used for the next step without furtherpurification. Mass spectral analysis: m/z=278 (M+H)⁺.

To a suspension of the resin 2a (preparation described in example 1) ina mixture dichloromethane/dimethylformamide 1:1 (20 mL) was addedconsecutively diisopropylethylamine (0.035 mL, 0.0002 mol, 1 eq),carboxylic acid 7 (0.056 g, 0.0002 mol, 1 eq), and HATU (0.076 g, 0.0002mol, 1 eq). The mixture was shaken for 6 hours at room temperature. Theresin was then drained, washed consecutively with dimethylformamide(5×), dimethylformamide/water (9:1) (5×), dimethylformamide (5×),methanol (5×), dichloromethane (5×), diethyl ether (5×) and dried undervacuum. The resin 8a was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (10 mL) at room temperature for 20 minutes.The filtrate was collected and the resin was further washed withdichloromethane (3×2 mL). Evaporation of the filtrate afforded thedesired compound further purified by routine HPLC. For Example 2 (9a),R⁸═(S) CH₂Ph; Mass spectral analysis: m/z=425 (M+H)⁺.

Example 32(S)-[{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-(4-methoxy-benzyl)-amino]-3-phenyl-propionicacid (14a)

To the resin 2a (0.00015 mol) swelled in trimethylorthoformate (6 mL)was added 4-methoxybenzaldehyde (0.408 g, 0.003 mol, 20 eq) and thereaction was mixed at room temperature for 30 min. Sodiumcyanoborohydride (0.19 0 g, 0.003 mol, 20 eq) dispersed intrimethylorthoformate (3 mL) was added followed by acetic acid (0.032mL), and the reaction mixture was mixed for an additional 10 min at roomtemperature. The reaction was filtered and the resin was washed withdimethylformamide (5×), methanol (5×), dichloromethane/triethylamine 9:1(5×), methanol (5×), dichloromethane (5×), methanol (5×), diethyl ether(5×) and dried under vacuum. To a suspension of the resin 10a obtainedpreviously in dichloromethane (20 mL) was added triethylamine (2.1 mL,0.0015 mol, 10 eq) followed by acryloyl chloride (0.12 mL, 0.0015 mol,10 eq). The mixture was shaken at room temperature for 6 hours. Theresin was then drained, washed consecutively with dimethylformamide(5×), dimethylformamide/water (9:1) (5×), dimethylformamide (5×),methanol (5×), dichloromethane (5×), diethyl ether (5×) and dried undervacuum. To a suspension of resin 11a obtained previously in MeOH/THF 1:2(20 mL) was added(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) (46 mg,0.00022 mol, 1.5 eq) and the mixture was stirred at room temperature for12 hours. The resin was then drained, washed consecutively withdimethylformamide (5×), dimethylformamide/water(9:1) (5×),dimethylformamide (5×), methanol (5×), dichloromethane (5×) andre-suspended in MeOH/THF 1:2 (20 mL).(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) (46 mg,0.00022 mol, 1.5 eq) was added to the mixture which was stirred at roomtemperature for an additional 12 hours. The resin was then drained,washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum.The resin 13a was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (10 mL) at room temperature for 20 min. Thefiltrate was collected and the resin was further washed withdichloromethane (3×2 mL). Evaporation of the filtrate afforded thedesired compound further purified by routine HPLC. For Example 3 (14a),R⁸═(S) CH₂Ph; R⁴=para-methoxybenzyl, R³═H; Mass spectral analysis:m/z=545 (M+H)⁺.

Example 4(S)-(Ethyl-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)-3-phenyl-propionicacid (20a)

A solution dimethylformamide/piperidine 20:80 (100 ML) was added to theFmoc-Phe Wang resin 1a (0.6 mmol/g, 3 g, 0.0018 mol) and the suspensionwas mixed at room temperature for 20 min. The resin was then drained,washed consecutively with dimethylformamide (5×),dimethylformamide/water(9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum.To a suspension of the resulting resin 2a in a mixturedichloromethane/tetrahydrofuran 1:3 (100 mL) was added consecutively2,6-lutidine (0.84 mL, 0.0072 mol, 4 eq) and 2,4-dinitrobenzenesulfonylchloride (1.92 g, 0.0072 mol, 4 eq). The mixture was shaken for 12 h atroom temperature. The resin was then drained, washed consecutively withdimethylformamide (5×), dimethylformamide/water (9:1) (5×),dimethylformamide (5×), methanol (5×), dichloromethane (5×), diethylether (5×) and dried under vacuum. To a suspension of the resultingresin 15a (0.200 g, 0.00012 mol, 1 eq) in tetrahydrofuran (20 mL) wasadded consecutively a 2M solution of triphenylphosphine intetrahydrofuran (0.6 mL, 0.0012 mol, 10 eq), a 2M solution ofdiisopropylazodicarboxylate (DIAD) in tetrahydrofuran (0.6 mL, 0.0012mol, 10 eq) and ethyl alcohol (0.055 g, 0.0012 mol, 10 eq). The mixturewas shaken for 12 h at room temperature. The resin was then drained,washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum. Asolution dimethylformamide/n-butylamine 80:20 (100 mL) was added to theresin 16a obtained previously and the suspension was mixed at roomtemperature for 6 hours (Scheme 4). The resin was then drained, washedconsecutively with dimethylformamide (5×), dimethylformamide/water (9:1)(5×), dimethylformamide (5×), methanol (5×), dichloromethane (5×),diethyl ether (5×) and dried under vacuum. To a suspension of theresulting resin 17a in dichloromethane (20 mL) was addeddidisopropylethylamine (0.21 mL, 0.0012 mol, 10 eq) followed by acryloylchloride (0.10 mL, 0.0012 mol, 10 eq). The mixture was shaken at roomtemperature for 6 hours. The resin was then drained, washedconsecutively with dimethylformamide (5×), dimethylformamide/water(9:1)(5×), dimethylformamide (5×), methanol (5×), dichloromethane (5×),diethyl ether (5×) and dried under vacuum. To a suspension of theresulting resin 18a in MeOH/THF 1:2 (20 mL) was added a 0.18M solutionof (+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) inMeOH/THF 1:2 (1 mL, 0.00018 mol, 1.5 eq) and the mixture was stirred atroom temperature for 12 hours. The resin was then drained, washedconsecutively with dimethylformamide (5×), dimethylformamide/water (9:1)(5×), dimethylformamide (5×), methanol (5×), dichloromethane (5×) andre-suspended in MeOH/THF 1:2 (20 mL). A 0.18M solution of(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) in MeOH/THF1:2 (1 mL, 0.00018 mol, 1.5 eq) was added to the mixture which wasstirred at room temperature for an additional 12 hours. The resin wasthen drained, washed consecutively with dimethylformamide (5×),dimethylformamide/water(9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum.The resin 19a was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (10 mL) at room temperature for 20 minutes.The filtrate was collected and the resin was further washed withdichloromethane (3×2 mL). Evaporation of the filtrate afforded thedesired compound further purified by routine HPLC. For Example 4 (20a),R⁸═(S) CH₂Ph; R³═H, R⁴═C₂H₅ ; Mass spectral analysis: m/z=(M+H)⁺.

Example 52(S)-(4-methoxyphenyl-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-phenyl-amino)-3-phenyl-propionicacid (24a)

The resin 2a (0.00015 mol) was swelled in dry tetrahydrofuran (5 mL) andthe following reagents were added in a sequential fashion:4-methoxyphenylboronic acid (0.091 g, 0.0006 mol, 4 eq), anhydrouscopper acetate (0.055 g, 0.0003 mol, 2 eq), 4Å powdered molecular sieves(0.170 g)and triethylamine (0.083 mL, 0.0006 mol, 4 eq). Theheterogeneous mixture was mixed for 16 h at room temperature. The resinwas filtered and was washed alternately with tetrahydrofuran (7×) anddichloromethane (5×) followed by tetrahydrofuran (5×). To a suspensionof the resin 21a obtained previously in dichloromethane (20 mL) wasadded diisopropylethylamine (0.26 mL, 0.0015 mol, 10 eq) followed byacryloyl chloride (0.12 mL, 0.0015 mol, 10 eq). The mixture was shakenat room temperature for 6 hours. The resin was then drained, washedconsecutively with dimethylformamide (5×), dimethylformamide/water (9:1)(5×), dimethylformamide (5×), methanol (5×), dichloromethane (5×),diethyl ether (5×) and dried under vacuum. To a suspension of resin 22aobtained previously in MeOH/THF 1:2 (20 mL) was added a 0.18M solutionof (+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) inMeOH/THF 1:2 (1 mL, 0.00018 mol, 1.5 eq) and the mixture was stirred atroom temperature for 12 hours. The resin was then drained, washedconsecutively with dimethylformamide (5×), dimethylformamide/water (9:1)(5×), dimethylformamide (5×), methanol (5×), dichloromethane (5×) andre-suspended in MeOH/THF 1:2 (20 mL). A 0.18M solution of(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (12) in MeOH/THF1:2 (1 mL, 0.00018 mol, 1.5 eq) was added to the mixture which wasstirred at room temperature for an additional 12 hours. The resin wasthen drained, washed consecutively with dimethylformamide (5×),dimethylformamide/water(9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethyl ether (5×) and dried under vacuum.The resin 23a was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (10 ML) at room temperature for 20 min. Thefiltrate was collected and the resin was further washed withdichloromethane (3×2 mL). Evaporation of the filtrate afforded thedesired compound further purified by routine HPLC. For Example 5 (24a),R⁸═(S) CH₂Ph; R⁴═CH₃OC₆H₄(p) ; Mass spectral analysis: m/z=531 (M+H)⁺.

Biological Assays

The potencies of the compounds were determined by testing the ability ofa range of concentrations of each compound to inhibit the binding of thenon-selective opioid antagonist, [³H]diprenorphine, to the cloned humanμ, κ, and δ opioid receptors, expressed in separate cell lines. IC₅₀values were obtained by nonlinear analysis of the data using GraphPadPrism version 3.00 for Windows (GraphPad Software, San Diego). K_(i)values were obtained by Cheng-Prusoff corrections of IC₅₀ values.

Receptor Binding (in vitro Assay)

The receptor binding method (DeHaven and DeHaven-Hudkins, 1998) was amodification of the method of Raynor et al. (1994). After dilution inbuffer A and homogenization as before, membrane proteins (10-80 μg) in250 μL were added to mixtures containing test compound and[³H]diprenorphine (0.5 to 1.0 nM, 40,000 to 50,000 dpm) in 250 μL ofbuffer A in 96-well deep-well polystyrene titer plates (Beckman). Afterincubation at room temperature for one hour, the samples were filteredthrough GF/B filters that had been presoaked in a solution of 0.5% (w/v)polyethylenimine and 0.1% (w/v) bovine serum albumin in water. Thefilters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH 7.8 andradioactivity remaining on the filters determined by scintillationspectroscopy. Nonspecific binding was determined by the minimum valuesof the titration curves and was confirmed by separate assay wellscontaining 10 μM naloxone. K_(i) values were determined by Cheng-Prusoffcorrections of IC₅₀ values derived from nonlinear regression fits of 12point titration curves using GraphPad Prism® version 3.00 for Windows(GraphPad Software, San Diego, Calif.).

To determine the equilibrium dissociation constant for the inhibitors(K_(i)), radioligand bound (cpm) in the presence of variousconcentrations of test compounds was measured. The concentration to givehalf-maximal inhibition (EC₅₀) of radioligand binding was determinedfrom a best nonlinear regression fit to the following equation,

$Y = {\text{Bottom} + \frac{\left( {\text{Top} - \text{Bottom}} \right)}{1 + 10^{X - {{Log}\;{EC50}}}}}$where Y is the amount of radioligand bound at each concentration of testcompound, Bottom is the calculated amount of radioligand bound in thepresence of an infinite concentration of test compound, Top is thecalculated amount of radioligand bound in the absence of test compound,X is the logarithm of the concentration of test compound, and LogEC₅₀ isthe log of the concentration of test compound where the amount ofradioligand bound is half-way between Top and Bottom. The nonlinearregression fit was performed using the program Prism® (GraphPadSoftware, San Diego, Calif.). The K_(i) values were then determined fromthe EC₅₀ values by the following equation,

$K_{i} = \frac{{EC}_{50}}{1 + \frac{\left\lbrack \text{ligand} \right\rbrack}{K_{d}}}$where [ligand] is the concentration of radioligand and K_(d) is theequilibrium dissociation constant for the radioligand.

The potencies of the antagonists were assessed by their abilities toinhibit agonist-stimulated [³⁵S]GTPγS binding to membranes containingthe cloned human μ, κ, or δ opioid receptors. The agonists used wereloperamide for the μ opioid receptor, U50488H for the κ opioid receptor,and BW373U86 for the δ opioid receptor.

To determine the IC₅₀ value, which was the concentration to givehalf-maximal inhibition of agonist-stimulated [³⁵S]GTPγS binding, theamount of [³⁵S]GTPγS bound in the presence of a fixed concentration ofagonist and various concentrations of antagonist was measured. The fixedconcentration of agonist was the EC₈₀ for the agonist, which was theconcentration to give 80% of the relative maximum stimulation of[³⁵S]GTPγS binding. The IC₅₀ value was determined from a best nonlinearregression fit of the data to the following equation,

$Y = {\text{Bottom} + \frac{\left( {\text{Top} - \text{Bottom}} \right)}{1 + 10^{X - {{Log}\;{IC50}}}}}$where Y is the amount of [³⁵S]GTPγS bound at each concentration ofantagonist, Bottom is the calculated amount of [³⁵S]GTPγS bound in thepresence of an infinite concentration of antagonist, Top is thecalculated amount of [³⁵S]GTPγS bound in the absence of addedantagonist, X is the logarithm of the concentration of antagonist, andLogIC₅₀ is the logarithm of the concentration of antagonist where theamount of [³⁵S]GTPγS bound is halfway between Bottom and Top. Thenonlinear regression fit was performed using GraphPad Prism® version3.00 for Windows (GraphPad Software, San Diego, Calif.).

The compounds described in Table 1 (Examples 1 to 82) were tested fortheir affinity towards the μ, δ and κ opioid receptors. All of thesecompounds bind with affinity less than 100 μM to the μ, δ and κ opioidreceptors. These compounds displayed various degree of selectivity μν.δ, ν. κ and κ ν. δ. The activity of selected ligands was also evaluatedin vitro. Numerous compounds were found to be pure antagonist at the μopioid receptor (no agonist activity detectable at concentration >10μM). As examples, compound 28 (Table 1) binds to the μ, δ and κ opioidreceptors with affinity (expressed as K_(i) value) of 0.4 nM, 510 nM and200 nM, respectively). Furthermore, the compound 28 displayed potent invitro antagonist activity (IC₅₀=1.4 nM). The compound 30 binds to the μ,δ and κ opioid receptors with affinity (expressed as K_(i) value) of 0.4nM, 860 nM and 440 nM, respectively). Furthermore, the compound 30displayed potent in vitro antagonist activity (IC₅₀=1.0 nM).

Mouse Gastrointestinal Transit (GIT) Assay (in vivo Assay)

The antagonist activity of compounds may be evaluated using the MouseGastrointestinal Transit (GIT) Assay (in vivo assay). Male Swiss-Webstermice (typically 25-30 g) are used for all experiments. Mice are housed4/cage in polycarbonate cages with food and water available ad libitum.Mice are on a 12 hours light:dark schedule with lights on at 6:30 a.m.All experiments are performed during the light cycle. Mice are fastedthe night before the experiment, with water available ad libitum.

Mice are administered vehicle (10% DMSO:20% Cremophor EL:70% saline) ortest compound (10 mg/kg) orally 2 or 6 hours before determination ofGIT. Compounds are administered in a volume of 0.1 ml/10 g of bodyweight. Morphine (3 mg/kg) or vehicle (0.9% saline) is administered s.c.35 minutes prior to determination of GIT. Ten minutes after the morphinetreatment, mice are administered 0.2 ml of a charcoal meal orally. Thecharcoal meal consists of a slurry of charcoal, flour, and water in thefollowing ratio (1:2:8, w:w:v). Twenty-five minutes after receiving thecharcoal meal, the mice are euthanized with CO₂ and GIT determined.

GIT is expressed as the % GIT by the following formula:

$\frac{\text{(distance~~to~~leading~~edge~~of~~charcoal~~meal~~(cm))}}{\text{(total~~length~~of~~the~~smal~~intestine~~(cm))}} \times 100.$For each compound a % Antagonism (% A) value is determined for the 2 and6-hour antagonist pretreatment. Using the mean % GIT for each treatmentgroup, % A is calculated using the following formula:

$1 - {\frac{\begin{matrix}{\text{((mean~~vehicle~~response} - \text{mean~~antagonist} +} \\\text{morphine~~response))}\end{matrix}}{\text{(mean~~vehicle~~response} - \text{mean~~morphine~~response)}} \times 100}$

TABLE 1 Ex- am- ple Name [M + H]⁺ 12(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5153(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3- phenyl-propionic acid2 2(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 425piperidin-1-yl]-propionylamino}-3-phenyl-propionic acid 32(S)-[{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 545piperidin-1-yl]-propionyl}-(4-methoxy-benzyl)- amino]-3-phenyl-propionicacid 4 2(S)-(Ethyl-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 453dimethyl-piperidin-1-yl]-propionyl}-amino)-3- phenyl-propionic acid 52(S)-({3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 531piperidin-1-yl]-propionyl}-phenyl-amino)-3-(4- methoxyphenyl)-propionicacid 6 2(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4393(R),4-dimethyl-piperidin-1-yl]-propionylamino}- propionic acid 71-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 465dimethyl-piperidin-1-yl]-propionyl}-pyrrolidine- 2(R)-carboxylic acid 86-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 481dimethyl-piperidin-1-yl]-propionylamino}-hexanoic acid 92(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5213(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3- cyclohexyl-propionicacid 10 {2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 507dimethyl-piperidin-1-yl]-propionylamino}-(S)- cyclohexyl-acetic acid 112(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5293(R),4-dimethyl-piperidin-1-yl]-propionylamino}-4- phenyl-butyric acid12 2(R)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5333(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(4-fluoro-phenyl)-propionic acid 132(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5603(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(4-nitro-phenyl)-propionic acid 14{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 501dimethyl-piperidin-1-yl]-propionylamino}-(R)- phenyl-acetic acid 15{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 501dimethyl-piperidin-1-yl]-propionylamino}-(S)- phenyl-acetic acid 162-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 527dimethyl-piperidin-1-yl]-propionyl}-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid 172(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5913(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-biphenyl-4-yl-propionic acid 182(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4993(R),4-dimethyl-piperidin-1-yl]-propionylamino}-4-methylsulfanyl-butyric acid 192(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5653(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-naphthalen-1-yl-propionic acid 202(R)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5663(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-naphthalen-1-yl-propionic acid 212(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5653(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-naphthalen-2-yl-propionic acid 222(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 6413(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(4-iodo-phenyl)-propionic acid 231-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 465dimethyl-piperidin-1-yl]-propionyl}-pyrrolidine-2- (S)-carboxylic acid24 3-(Acetylamino-methylsulfanyl)-2(S)-{2(S)-benzyl- 5423-[4(R)-(3-hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionylamino}-propionic acid 253-(4-Benzoyl-phenyl)-2(S)-{2(S)-benzyl-3-[4(R)-(3- 619hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionylamino}-propionic acid 262(R)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4393(R),4-dimethyl-piperidin-1-yl]-propionylamino}- propionic acid 272(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4833(R),4-dimethyl-piperidin-1-yl]-propionylamino}- succinic acid 285-Amino-2(S)-{2(S)-benzyl-3-[4(R)-(3-hydroxy- 482phenyl)-3(R),4-dimethyl-piperidin-1-yl]- propionylamino}-pentanoic acid29 2(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4553(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3- hydroxy-propionicacid 30 6-Amino-2(S)-{2(S)-benzyl-3-[4(R)-(3-hydroxy- 496phenyl)-3(R),4-dimethyl-piperidin-1-yl]- propionylamino}-hexanoic acid31 3-Amino-2(S)-{2(S)-benzyl-3-[4(R)-(3-hydroxy- 454phenyl)-3(R),4-dimethyl-piperidin-1-yl]- propionylamino}-propionic acid32 2(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 4973(R),4-dimethyl-piperidin-1-yl]-propionylamino}- pentanedioic acid 332(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5543(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(1H-indol-3-yl)-propionic acid 341-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 481dimethyl-piperidin-1-yl]-propionyl}-4(R)-hydroxy-pyrrolidine-2(R)-carboxylic acid 352(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5313(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(4-hydroxy-phenyl)-propionic acid 362(S)-{2(S)-Benzyl-3-[4(R)-(3-hydroxy-phenyl)- 5053(R),4-dimethyl-piperidin-1-yl]-propionylamino}-3-(1H-imidazol-4-yl)-propionic acid 372-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 437piperidin-1-yl]-propionyl}-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid 383-(4-Fluoro-phenyl)-2(R)-{3-[4(R)-(3-hydroxy- 443phenyl)-3(R),4-dimethyl-piperidin-1- yl]propionylamino}-propionic acid39 3-Cyclohexyl-2(S)-{3-[4(R)-(3-hydroxy-phenyl)- 4313(R),4-dimethyl-piperidin-1-yl]-propionylamino}- propionic acid 40(S)-Cyclohexyl-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 417dimethyl-piperidin-1-yl]-propionylamino}-acetic acid 412(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 439piperidin-1-yl]-propionylamino}-4-phenyl-butyric acid 422(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 470piperidin-1-yl]-propionylamino}-3-(4-nitro-phenyl)- propionic acid 432(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 475piperidin-1-yl]-propionylamino}-3-naphthalen-1-yl- propionic acid 442(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 551piperidin-1-yl]-propionylamino}-3-(4-iodo-phenyl)- propionic acid 453-(4-Benzoyl-phenyl)-2(S)-{3-[4(R)-(3-hydroxy- 529phenyl)-3(R),4-dimethyl-piperidin-1-yl]- propionylamino}-propionic acid46 6-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 391piperidin-1-yl]-propionylamino}-hexanoic acid 472(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 409piperidin-1-yl]-propionylamino}-4-methylsulfanyl- butyric acid 482(R)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 475piperidin-1-yl]-propionylamino}-3-naphthalen-1-yl- propionic acid 492(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 475piperidin-1-yl]-propionylamino}-3-naphthalen-2-yl- propionic acid 50{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 411piperidin-1-yl]-propionylamino}-(S)-phenyl-acetic acid 512(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 393piperidin-1-yl]-propionylamino}-succinic acid 522(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 407piperidin-1-yl]-propionylamino}-pentanedioic acid 535-Amino-2(S)-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 392dimethyl-piperidin-1-yl]-propionylamino}-pentanoic acid 546-Amino-2(S)-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 406dimethyl-piperidin-1-yl]-propionylamino}-hexanoic acid 553-Amino-2(S)-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 364dimethyl-piperidin-1-yl]-propionylamino}-propionic acid 562(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 392piperidin-1-yl]-propionylamino}-succinamic acid 572(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 464piperidin-1-yl]-propionylamino}-3-(1H-indol-3-yl)- propionic acid 584(R)-Hydroxy-1-{3-[4(R)-(3-hydroxy-phenyl)- 3913(R),4-dimethyl-piperidin-1-yl]-propionyl}- pyrrolidine-2(R)-carboxylicacid 59 3-(4-Hydroxy-phenyl)-2(S)-{3-[4(R)-(3-hydroxy- 441phenyl)-3(R),4-dimethyl-piperidin-1-yl]- propionylamino}-propionic acid60 2(S)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 415piperidin-1-yl]-propionylamino}-3-(1H-imidazol-4- yl)-propionic acid 611-{3-[4-(3-Hydroxy-phenyl)-3,4-dimethyl-piperidin- 3751-yl]-propionyl}-pyrrolidine-2(R)-carboxylic acid 623-(Acetylamino-methylsulfanyl)-2(S)-{3-[4(R)-(3- 452hydroxy-phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionylamino}-propionic acid 633-Hydroxy-2(S)-{3-[4(R)-(3-hydroxy-phenyl)- 3653(R),4-dimethyl-piperidin-1-yl]-propionylamino}- propionic acid 644-Carbamoyl-2(S)-{3-[4(R)-(3-hydroxy-phenyl)- 4063(R),4-dimethyl-piperidin-1-yl]-propionylamino}- butyric acid 652(R)-{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 349piperidin-1-yl]-propionylamino}-propionic acid 663-Biphenyl-4-yl-2(S)-{3-[4(R)-(3-hydroxy-phenyl)- 5013(R),4-dimethyl-piperidin-1-yl]-propionylamino}- propionic acid 672(S)-((3-Benzyloxy-benzyl)-{3-[4(R)-(3-hydroxy- 621phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)-3-phenyl-propionic acid 682(S)-(Biphenyl-4-ylmethyl-{3-[4(R)-(3-hydroxy- 591phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)-3-phenyl-propionic acid 692(S)-((3-Chloro-benzyl)-{3-[4(R)-(3-hydroxy- 549phenyl)-3(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)-3-phenyl-propionic acid 702(S)-[{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 607piperidin-1-yl]-propionyl}-(3-phenoxy-benzyl)- amino]-3-phenyl-propionicacid 71 2(S)-({3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 439piperidin-1-yl]-propionyl}-methyl-amino)-3-phenyl- propionic acid 722(S)-({3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 481piperidin-1-yl]-propionyl}-isobutyl-amino)-3-phenyl- propionic acid 732(S)-(Cyclopropylmethyl-{3-[4(R)-(3-hydroxy- 479phenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl}-amino)-3-phenyl-propionic acid 742(S)-(Hex-3-enyl-{3-[4(R)-(3-hydroxy-phenyl)- 5073(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)- 3-phenyl-propionicacid 75 2(S)-({3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 529piperidin-1-yl]-propionyl}-phenethyl-amino)-3- phenyl-propionic acid 762(S)-(Benzyl-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4- 515dimethyl-piperidin-1-yl]-propionyl}-amino)-3- phenyl-propionic acid 772(S)-[{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 538piperidin-1-yl]-propionyl}-(2-morpholin-4-yl-ethyl)-amino]-3-phenyl-propionic acid 782(S)-((2-Amino-ethyl)-{3-[4(R)-(3-hydroxy-phenyl)- 4683(R),4-dimethyl-piperidin-1-yl]-propionyl}-amino)- 3-phenyl-propionicacid 79 2(S)-({3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 501piperidin-1-yl]-propionyl}-phenyl-amino)-3-phenyl- propionic acid 802(S)-[{3-[4(R)-(3-Hydroxy-phenyl)-3(R),4-dimethyl- 559piperidin-1-yl]-propionyl}-(3-phenoxy-benzyl)-amino]-3-(4-methoxycarbonylphenyl)-propionic acid 812S-Benzyl-3-[4-(3-hydroxy-phenyl)-3R,4R-dimethyl- 499piperidin-1-yl]-N-trifluoromethylsulfonyl- propionamide 82({2S-Benzyl-3-[4-(3-hydroxy-phenyl)-3R,4R- 461dimethyl-piperidin-1-yl]-propionylamino}-methyl)- phosphonic acid

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of formula I:

wherein: R¹ is H or C₁-C₆alkyl; R^(2a) is C₁-C₆alkyl or C₂-C₆alkenyl;R^(2b) is H, C₁-C₆alkyl, or C₂-C₆alkenyl; R³ is H, unsubstitutedC₁-C₆alkyl, or unsubstituted benzyl; R⁵ is —(CHR⁸)—W; R⁴ and R⁸ whentaken together with the atoms through which they are connected, form apyrrolidine or tetrahydroisoquinoline ring, wherein said pyrrolidine ortetrahydroisoquinoline ring is optionally substituted by one or moresubstituents selected from —OH, unsubstituted C₁-C₆alkyl, orunsubstituted C₁-C₆alkoxy; W is —C(═O)OR⁹; R⁹ is H, C₁-C₆alkyl,C₂-C₆alkenyl, phenyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl,C₃-C₈cycloalkylC₁-C₃alkyl, C₅-C₈cycloalkenylC₁-C₃alkyl, orC₆-C₁₀arylC₁-C₄alkyl; m is the integer 0, 1, 2, 3, or 4; and q is theinteger 0, 1, or 2; or a stereoisomer, pharmaceutically acceptable salt,or N-oxide thereof.
 2. A compound according to claim 1, wherein R¹ is H.3. A compound according to claim 1, wherein R^(2a) and R^(2b) are transto each other.
 4. A compound according to claim 1, of formula II:


5. A compound according to claim 1, wherein R^(2a) and R^(2b) are eachmethyl.
 6. A compound according to claim 1, of formula III:


7. A compound according to claim 1, wherein R³ is:


8. A compound according to claim 1, of formula V:


9. A compound according to claim 8, of formula VII:


10. A compound according to claim 9, wherein R³ is:


11. A compound according to claim 10, wherein R^(2a) and R^(2b) are eachmethyl.
 12. A compound according to claim 11, of formula VIIa:


13. A compound according to claim 11, of formula VIIb:


14. A compound according to claim 1, wherein W is —CO₂H.
 15. A compoundaccording to claim 1, wherein m is the integer
 1. 16. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier; and aneffective amount of a compound according to claim
 1. 17. A compoundaccording to claim 1, which is selected from the group consisting of:1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2(R)-carboxylic acid;2-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl}-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid;1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2-(S)-carboxylic acid;1-{2(S)-Benzyl-3-[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl}-4(R)-hydroxypyrrolidine-2(R)-carboxylic acid;2-{3-[4(R)-(3-Hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl}-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid;4(R)-Hydroxy-1-{3[4(R)-(3-hydroxyphenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl }pyrrolidine-2(R)-carboxylic acid;and 1-{3-[4-(3-Hydroxyphenyl)-3 ,4-dimethylpiperidin-1-yl]-propionyl}pyrrolidine-2(R)-carboxylic acid; or a stereoisomer, pharmaceuticallyacceptable salt, or N-oxide thereof.
 18. A compound according to claim17 which is 4(R)-Hydroxy-1-{3-[4(R)-(3-hydroxy-phenyl)-3(R),4-dimethylpiperidin-1-yl]-propionyl}pyrrolidine-2(R)-carboxylicacid.